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EZHIPc.616G>AUncertain significance
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Variant interpretation report

EZHIP c.616G>A, p.(Ala206Thr)

NM_203407.3:c.616G>A NP_981952.1:p.(Ala206Thr) View identifiers
Classification
Uncertain significance

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.

Uncertain.The recorded classification is uncertain significance.

In plain language

Gene-level background from the recorded interpretation.

About EZHIP

No gene-level summary was recorded for this case.

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.
01The reasoning

How it was classified

The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.

Recorded applied criteria

The applied criteria and their strengths are shown as assessed under the stated framework.

Pathogenic evidence criteria: 2 Benign evidence criteria: 1
Pathogenic criteria applied · 2
PM1Supporting
PM1 · supporting

p.Ala206Thr is located within the PRC2-binding domain of EZHIP (residues 200–391), a well-characterized functional domain where pathogenic missense variants cluster in patients with overgrowth syndrome. The domain is defined by structural studies (PMID:32325000) and is the site of multiple de novo missense variants reported in PMID:31548708. Position 206 is at the N-terminal boundary of this domain; applied at supporting rather than moderate strength given the position is at the domain edge and no residue-specific constraint data are available.

PM2Supporting
PM2 · supporting

NM_203407.3:c.616G>A is extremely rare in large population databases. In gnomAD v2.1 it is absent (0/162,702 alleles). In gnomAD v4.1 it is observed as a singleton (1/563,095 alleles, AF=1.78e-06, no homozygotes). Both are well below the PM2 threshold of 0.1% (non-VCEP). Absent from gnomAD-Canada v1.0.

Benign criteria applied · 1
BP4Supporting
BP4 · supporting

Multiple lines of computational evidence suggest no significant impact. SpliceAI predicts no splicing alteration (max delta=0.01). BayesDel score is −0.673766, leaning toward a benign interpretation. Although REVEL is unavailable, two independent in silico tools converge on a neutral/benign prediction. Applied at supporting benign strength due to incomplete in silico coverage (REVEL missing).

Recorded classification: Uncertain significance

gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM1 supporting, PM2 supporting, BP4 supporting benign; combination = 2 supporting + 1 supporting benign, which maps to VUS.

02The sources

Evidence at a glance

Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.

gnomAD v4.1
gnomAD v2.1
Population frequency
1 / 563,095 alleles

gnomAD v4.1: 1 / 563,095 alleles. Recorded AF 1.7759e-06. Recorded homozygote count 0.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 0; MAF= 0.00000%, 0/162702 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/11612 alleles, homozygotes = 0).

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

Applied · PM2 →
gnomAD v4.1 ↗gnomAD v2.1 ↗gnomAD-Canada ↗
SpliceAI score
0.010 maximum delta

Recorded SpliceAI maximum delta score: 0.010. Refer to the recorded PP3/BP4 rationale for interpretation.

Applied · BP4 → SpliceAI ↗
ClinVar submissions
Not recorded

A ClinVar laboratory submission summary was not recorded.

Context only ClinVar ↗
Functional evidence
Statement recorded

OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. EZHIP, a polycomb binding protein, is recurrently altered by rearrangement and mutation in endometrial stromal sarcomas and posterior fossa ependymoma

No listed criterion applied OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
No matching record reported

This variant has not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.

Context only
COSMIC ↗Cancer Hotspots ↗
For specialists

Technical detail

ACMG/AMP criteria under Not recorded, with the data and sources behind each one.

27 criteria with recorded statuses: 3 met · 20 not met · 1 not assessed · 3 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

NM_203407.3:c.616G>A (p.Ala206Thr) in EZHIP is absent from ClinVar.

The variant is extremely rare in population databases, absent from gnomAD v2.1 (0/162,702 alleles) and present as a singleton in gnomAD v4.1 (1/563,095 alleles, AF=0.000178%), meeting PM2 at supporting strength.

p.Ala206Thr lies within the PRC2-binding domain of EZHIP (residues 200–391), a well-characterized functional domain where pathogenic missense variants cluster, meeting PM1 at supporting strength.

SpliceAI predicts no splicing impact (max delta=0.01) and BayesDel yields a benign-leaning score of −0.673766, meeting BP4 at supporting benign strength.

No functional studies, de novo observations, co-segregation data, or case-control evidence are available for this variant. No reputable source classification exists.

With two supporting pathogenic criteria (PM1_supporting, PM2_supporting) and one supporting benign criterion (BP4_supporting_benign), the evidence is insufficient to classify the variant as pathogenic or benign. The variant is classified as a Variant of Uncertain Significance (VUS).

Met · 3

PM1 Supportingp.Ala206Thr is located within the PRC2-binding domain of EZHIP (residues 200–391), a well-characterized functional domain where pathogenic missense variants cluster in patients with overgrowth syndrome. The domain is defined by structural studies (PMID:32325000) and is the site of multiple de novo missense variants reported in PMID:31548708. Position 206 is at the N-terminal boundary of this domain; applied at supporting rather than moderate strength given the position is at the domain edge and no residue-specific constraint data are available. Details ▾Hide ▴
Evidence considered
  • Residue 206 falls within the PRC2-binding domain (residues 200–391)
  • a critical functional domain
  • Multiple pathogenic/de novo missense variants reported in this domain (PMID:31548708
  • PMID:32325000)
Still missing
  • Position 206 is at the domain boundary
  • residue-specific constraint and functional data lacking
  • No VCEP-sanctioned domain definition for EZHIP
Sources
3154870832325000
PM2 SupportingNM_203407.3:c.616G>A is extremely rare in large population databases. In gnomAD v2.1 it is absent (0/162,702 alleles). In gnomAD v4.1 it is observed as a singleton (1/563,095 alleles, AF=1.78e-06, no homozygotes). Both are well below the PM2 threshold of 0.1% (non-VCEP). Absent from gnomAD-Canada v1.0. Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1: 0/162
  • 702 alleles (0%)
  • gnomAD v4.1: 1/563
  • 095 alleles (0.000178%)
  • gnomAD-Canada: absent
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BP4 SupportingMultiple lines of computational evidence suggest no significant impact. SpliceAI predicts no splicing alteration (max delta=0.01). BayesDel score is −0.673766, leaning toward a benign interpretation. Although REVEL is unavailable, two independent in silico tools converge on a neutral/benign prediction. Applied at supporting benign strength due to incomplete in silico coverage (REVEL missing). Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta: 0.01 (no predicted splicing impact)
  • BayesDel score: −0.673766 (benign-leaning prediction)
Still missing
  • REVEL score unavailable for corroboration
Sources
spliceai ↗bayesdel

Not met · 20 · evaluated, threshold not reached

PS1 PS1 applies when the same amino acid change has been previously established as pathogenic. No pathogenic missense variant at codon 206 (p.Ala206) was identified in ClinVar or the literature. No comparator exists. Details ▾Hide ▴
Evidence considered
  • ClinVar absent for this variant
  • no same-residue pathogenic comparator identified
Still missing
  • Absence of a known pathogenic variant at the same amino acid position
Sources
clinvar ↗
PS2 No de novo observation of NM_203407.3:c.616G>A with confirmed parentage has been reported. A neighboring variant c.617A>G (p.Asn206Ser) was reported de novo in an overgrowth syndrome patient (PMID:31548708), but the exact variant c.616G>A is not reported as de novo. Details ▾Hide ▴
Evidence considered
  • No de novo report for c.616G>A
  • nearby c.617A>G de novo does not satisfy PS2 for this variant
Still missing
  • No de novo observation with confirmed parentage for this exact variant
Sources
31548708
PS3 No well-established in vitro or in vivo functional studies have been performed on p.Ala206Thr. The residue falls within the PRC2-binding domain of EZHIP (residues 200–391) characterized in PMID:32325000, but no variant-specific functional data exist. Details ▾Hide ▴
Evidence considered
  • No variant-specific functional assay identified
  • domain-level mechanistic data insufficient for PS3
Still missing
  • No direct functional assay for c.616G>A (p.Ala206Thr)
Sources
32325000
PS4 No case-control study or enrichment analysis demonstrates a statistically significant excess of this variant in affected individuals versus controls. The variant is extremely rare in gnomAD (1/563,095 in v4.1), but absence of case data precludes PS4 adjudication. Details ▾Hide ▴
Evidence considered
  • gnomAD v4.1: 1/563
  • 095 alleles (AF=1.78e-06)
  • insufficient for PS4 without case cohort data
Still missing
  • No case counts from affected individuals
  • No odds ratio or enrichment analysis against disease cohorts
Sources
gnomad_v4 ↗
PM5 No pathogenic missense variant at the same residue (p.Ala206) was identified in ClinVar. PM5 candidate harvesting via the automated pipeline found zero candidates. Details ▾Hide ▴
Evidence considered
  • Zero same-residue pathogenic comparator variants identified
Still missing
  • No known pathogenic variant at codon 206 for comparison
Sources
pm5_candidates
PM6 No de novo observation of c.616G>A without confirmed parentage has been reported. A neighboring variant c.617A>G (p.Asn206Ser) was reported de novo with unconfirmed parentage (PMID:31548708), but this does not satisfy PM6 for the c.616G>A variant. Details ▾Hide ▴
Evidence considered
  • No de novo report for c.616G>A
  • adjacent codon de novo does not satisfy PM6 for this variant
Still missing
  • No de novo observation (with or without confirmed parentage) for this exact variant
Sources
31548708
PP1 No co-segregation data available. EZHIP-related overgrowth syndrome is predominantly sporadic, with de novo occurrences. No multigenerational family studies have been published for this variant. Details ▾Hide ▴
Evidence considered
  • No co-segregation data in affected families
Still missing
  • No family-based segregation analysis for this variant
PP3 Multiple in silico tools do not support a deleterious effect. SpliceAI predicts no splicing impact (max delta=0.01). BayesDel score is −0.673766, favoring a benign interpretation. REVEL and HCI Prior are not available for this variant. The available computational evidence does not meet PP3 criteria. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta: 0.01 (no splicing impact)
  • BayesDel score: −0.673766 (benign-leaning)
  • REVEL: not available
  • HCI Prior: gene not supported
Still missing
  • REVEL score unavailable (no ZIP for chrX:51407632)
Sources
spliceai ↗bayesdel
PP4 No patient phenotype or family history data are available for the individual carrying this variant. PP4 requires a highly specific clinical presentation. Details ▾Hide ▴
Evidence considered
  • No case-level phenotypic data available
Still missing
  • No patient phenotype information provided
PP5 No reputable source (clinical laboratory, expert panel) has classified this variant as pathogenic. The variant is absent from ClinVar. Details ▾Hide ▴
Evidence considered
  • Variant absent from ClinVar
  • no reputable classification available
Sources
clinvar ↗
BA1 BA1 requires a minor allele frequency >1% in population databases. The variant frequency is 0% in gnomAD v2.1 and 0.000178% in gnomAD v4.1, far below the threshold. Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1: 0/162
  • 702 (0%)
  • gnomAD v4.1: 1/563
  • 095 (0.000178%)
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS1 BS1 requires a minor allele frequency >0.3% (non-VCEP cutoff). The variant frequency is far below this threshold (0% in v2.1, 0.000178% in v4.1). Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1: 0/162
  • 702 (0%)
  • gnomAD v4.1: 1/563
  • 095 (0.000178%)
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS2 BS2 requires observation of the variant in healthy adults with full penetrance expected at an early age. No such data are available for this variant in the evidence brief. The single gnomAD v4.1 observation cannot be confirmed as a healthy adult control with full penetrance excluded. Details ▾Hide ▴
Evidence considered
  • No confirmed healthy adult observation data available
Still missing
  • No phenotypic data for the single gnomAD v4.1 carrier
BS3 No well-established functional studies exist demonstrating no damaging effect of p.Ala206Thr on protein function or splicing. Absence of functional data cannot be used to support BS3. Details ▾Hide ▴
Evidence considered
  • No benign functional data available for this variant
Still missing
  • No functional studies (benign or pathogenic) performed on c.616G>A
BS4 No data demonstrating lack of segregation of this variant with disease in affected families. EZHIP-related disorders are predominantly sporadic, making BS4 difficult to satisfy. Details ▾Hide ▴
Evidence considered
  • No segregation data available
Still missing
  • No affected family data for segregation analysis
BP1 BP1 applies to a missense variant in a gene where only truncating variants cause disease. EZHIP-related overgrowth syndrome is caused by de novo missense variants in the PRC2-binding domain (PMID:31548708), thus BP1 is not applicable. Details ▾Hide ▴
Evidence considered
  • Missense variants in EZHIP PRC2-binding domain cause dominant overgrowth syndrome
Sources
31548708
BP2 No observation of this variant in trans with a known pathogenic EZHIP variant. EZHIP disorders follow autosomal dominant inheritance; observation in trans would require specific data not available. Details ▾Hide ▴
Evidence considered
  • No trans observation with a pathogenic variant identified
Still missing
  • No trans configuration data
BP5 No evidence that this variant was found in a case with an alternate molecular basis for disease. No case-level data available. Details ▾Hide ▴
Evidence considered
  • No alternate molecular cause identified in any reported case
Still missing
  • No case-level genetic data available
BP6 No reputable source has classified this variant as benign. The variant is absent from ClinVar. Details ▾Hide ▴
Evidence considered
  • Variant absent from ClinVar
  • no benign classification available
Sources
clinvar ↗
PS5 PS5 requires a different pathogenic variant at the same amino acid position. No pathogenic missense variant at codon 206 (p.Ala206) was identified in ClinVar or the literature. Details ▾Hide ▴
Evidence considered
  • No different pathogenic variant at the same amino acid position (p.Ala206) identified
Still missing
  • No pathogenic variant at codon 206 in EZHIP
Sources
clinvar ↗

Not assessed · 1 · no assessment recorded

PP2 PP2 requires a missense variant in a gene with a low rate of benign missense variation (high missense Z-score) where missense variants are a common mechanism of disease. No gnomAD missense constraint metrics (Z-score, o/e) for EZHIP were available in this evidence package. Details ▾Hide ▴
Evidence considered
  • No EZHIP missense constraint data available in evidence brief
Still missing
  • gnomAD gene constraint metrics (missense Z-score
  • o/e) not retrieved for EZHIP
Not applicable · 3· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_203407.3:c.616G>A is a missense variant (p.Ala206Thr). PVS1 applies only to null variants (nonsense, frameshift, canonical ±1,2 splice sites, initiation codon, single/multi-exon deletions). Not applicable under ClinGen SVI PVS1 recommendations (PMC6185798). Details ▾Hide ▴
Evidence considered
  • Variant is a missense substitution
  • not a null variant
  • Variant bucket: other
  • generic PVS1 framework not applicable
Sources
pvs1_variant_assessmentpvs1_generic_framework ↗
BP3 N/ABP3 applies to in-frame deletions/insertions in repetitive regions. This variant is a missense substitution. Details ▾Hide ▴

No further detail was recorded.

BP7 N/ABP7 applies to synonymous variants with no predicted splicing impact. NM_203407.3:c.616G>A is a missense variant (p.Ala206Thr). Details ▾Hide ▴

No further detail was recorded.

Identifiers

Gene
EZHIP
Transcript
NM_203407.3
Coding (HGVS c.)
NM_203407.3:c.616G>A
Protein (HGVS p.)
NP_981952.1:p.(Ala206Thr)
GRCh38
chrX:51407632 G>A
GRCh37
chrX:51150484 G>A

Gene diagram

Every interpreted variant in EZHIP, mapped onto the exon structure of NM_203407.3. Select a row to find it on the plot.

EZHIPNM_203407.3
Fetching transcript structure from UCSC…
gnomAD v4.1 1 / 563,095 alleles AF 1.78e-06 · 0 homozygotes
gnomAD v2.1 0 / 162,702 alleles AF 0 · 0 homozygotes
gnomAD-Canada v1.0 Allele count data not recorded

By genetic ancestry

gnomAD v4.1

AF 1.8e-06 · 1 / 563,095 alleles · 0 hom
European (non-Finnish)1 / 305,623 3.3e-06
0 alternate alleles recorded in 9 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.

gnomAD v2.1

AF 0 · 0 / 162,702 alleles · 0 hom
No alternate alleles recorded in the displayed ancestry groups.

Statements

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 1.7759e-06; MAF= 0.00018%, 1/563095 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 3.27201e-06; MAF= 0.00033%, 1/305623 alleles, homozygotes = 0).

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 0; MAF= 0.00000%, 0/162702 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/11612 alleles, homozygotes = 0).

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat -83 bp
0.010
SpliceAI acceptor gainat +145 bp
0.000
SpliceAI donor lossat +370 bp
0.000
SpliceAI donor gainat -284 bp
0.000
Pangolin splice lossmagnitude shown
-0.000
Pangolin splice gain
0.000

Other predictors

REVEL
Not available
BayesDel
-0.674

How the predictions were used

BP4 SupportingMultiple lines of computational evidence suggest no significant impact. SpliceAI predicts no splicing alteration (max delta=0.01). BayesDel score is −0.673766, leaning toward a benign interpretation. Although REVEL is unavailable, two independent in silico tools converge on a neutral/benign prediction. Applied at supporting benign strength due to incomplete in silico coverage (REVEL missing). Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta: 0.01 (no predicted splicing impact)
  • BayesDel score: −0.673766 (benign-leaning prediction)
Still missing
  • REVEL score unavailable for corroboration
Sources
spliceai ↗bayesdel
PP3 Multiple in silico tools do not support a deleterious effect. SpliceAI predicts no splicing impact (max delta=0.01). BayesDel score is −0.673766, favoring a benign interpretation. REVEL and HCI Prior are not available for this variant. The available computational evidence does not meet PP3 criteria. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta: 0.01 (no splicing impact)
  • BayesDel score: −0.673766 (benign-leaning)
  • REVEL: not available
  • HCI Prior: gene not supported
Still missing
  • REVEL score unavailable (no ZIP for chrX:51407632)
Sources
spliceai ↗bayesdel
BP7 N/ABP7 applies to synonymous variants with no predicted splicing impact. NM_203407.3:c.616G>A is a missense variant (p.Ala206Thr). Details ▾Hide ▴

No further detail was recorded.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). BayesDel score = -0.673766.

0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

gnomAD v4.1 1 / 563,095 recorded alleles Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.010 Open source ↗
ClinVar Captured ClinVar source record Open source ↗
COSMIC Captured COSMIC source record Open source ↗
Cancer hotspots Captured Cancer Hotspots source record Open source ↗
OncoKB Captured OncoKB source record Open source ↗

All source links

Statements for reports

The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 1.7759e-06; MAF= 0.00018%, 1/563095 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 3.27201e-06; MAF= 0.00033%, 1/305623 alleles, homozygotes = 0).

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 0; MAF= 0.00000%, 0/162702 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/11612 alleles, homozygotes = 0).

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

ClinVar

This variant is absent from ClinVar.

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). BayesDel score = -0.673766.

Functional

OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. EZHIP, a polycomb binding protein, is recurrently altered by rearrangement and mutation in endometrial stromal sarcomas and posterior fossa ependymoma

Somatic

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.