EZHIPc.162C>TUncertain significance

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Variant interpretation report

EZHIP c.162C>T, p.(Pro54=)

NM_203407.3:c.162C>T NP_981952.1:p.(Pro54=) 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.

Key facts

Evidence used: 1 supporting (benign) · 1 supporting (pathogenic)
Expert rules: Not recorded
Pipeline record: 26 Jun 2026 · version 7.0.0

Evidence considered

View criteria

Applied evidence criteria

PM2 (supporting): This variant is present in gnomAD v4.1 at an extremely low allele frequency of 0.00018% (1/570,831 alleles, 0 homozygotes) and is absent from gnomAD v2.1 and gnomAD-Canada, meeting the <0.1% threshold.
BP7 (supporting): NM_203407.3:c.162C>T is a synonymous variant (p.Pro54=) and SpliceAI predicts no impact on splicing (max delta score = 0.00). Nucleotide-level conservation has not been explicitly assessed.

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: 1 Benign evidence criteria: 1

Pathogenic criteria applied · 1

PM2Supporting

PM2 · supporting

This variant is present in gnomAD v4.1 at an extremely low allele frequency of 0.00018% (1/570,831 alleles, 0 homozygotes) and is absent from gnomAD v2.1 and gnomAD-Canada, meeting the <0.1% threshold.

Benign criteria applied · 1

BP7Supporting

BP7 · supporting

NM_203407.3:c.162C>T is a synonymous variant (p.Pro54=) and SpliceAI predicts no impact on splicing (max delta score = 0.00). Nucleotide-level conservation has not been explicitly assessed.

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: PM2 supporting, BP7 supporting benign; combination = 1 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 / 570,831 alleles

gnomAD v4.1: 1 / 570,831 alleles. Recorded AF 1.75183e-06. Recorded homozygote count 0.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

Applied · PM2 →

gnomAD v4.1 ↗gnomAD v2.1 ↗gnomAD-Canada ↗

SpliceAI score

0.000 maximum delta

Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.

Applied · BP7 → SpliceAI ↗

ClinVar submissions

Not recorded

A ClinVar laboratory submission summary was not recorded.

Context only ClinVar ↗

Functional evidence

Statement recorded

OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.

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.

29 criteria with recorded statuses: 2 met · 8 not met · 12 not assessed · 7 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic

PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 PS5

Benign

BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7

Met Not met Not assessed Not applicable

NM_203407.3:c.162C>T (p.Pro54=) is a synonymous variant in EZHIP with no predicted splice impact (SpliceAI max delta = 0.00) and is present at extremely low frequency in gnomAD v4.1 (1/570,831 alleles).

BP7 (supporting benign) is met: the variant is synonymous and SpliceAI predicts no splicing impact.

PM2 (supporting) is met: the variant is present at 0.00018% in gnomAD v4.1, below the 0.1% threshold.

One supporting benign criterion (BP7) and one supporting pathogenic criterion (PM2) are met; these do not combine to a definitive classification under generic ACMG/AMP 2015 rules. The variant is classified as a Variant of Uncertain Significance (VUS).

Met · 2

PM2 SupportingThis variant is present in gnomAD v4.1 at an extremely low allele frequency of 0.00018% (1/570,831 alleles, 0 homozygotes) and is absent from gnomAD v2.1 and gnomAD-Canada, meeting the <0.1% threshold. Details ▾Hide ▴

Evidence considered

gnomAD v4.1: AF = 1.75e-06 (1/570
831 alleles
0 homozygotes)
gnomAD v2.1: absent
gnomAD-Canada v1.0: absent

Sources

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

BP7 SupportingNM_203407.3:c.162C>T is a synonymous variant (p.Pro54=) and SpliceAI predicts no impact on splicing (max delta score = 0.00). Nucleotide-level conservation has not been explicitly assessed. Details ▾Hide ▴

Evidence considered

Synonymous substitution (CCC→CCT
both encode Proline)
SpliceAI max delta = 0.00 — no splice impact predicted.

Still missing

Nucleotide conservation not explicitly assessed.

Sources

spliceai ↗

Not met · 8 · evaluated, threshold not reached

PS1 No previously established pathogenic variant with the same amino acid change exists for this residue; the variant is absent from ClinVar and no literature reports a pathogenic synonymous change at codon 54. Details ▾Hide ▴

Evidence considered

Variant absent from ClinVar
no pathogenic synonymous variant at this codon identified in any database.

Sources

clinvar ↗

PM1 This variant does not lie in a statistically significant mutational hotspot, and no critical functional domain has been defined where missense variation is enriched in disease. Details ▾Hide ▴

Evidence considered

Hotspot analysis: variant not in a significant hotspot region.

PP3 SpliceAI predicts no splicing impact (max delta = 0.00), and REVEL and BayesDel scores are unavailable for this variant. No in silico tool predicts a deleterious effect. Details ▾Hide ▴

Evidence considered

SpliceAI max delta = 0.00 (no predicted splice impact)
REVEL: not available for this genomic position
BayesDel: not available for this genomic position

Still missing

REVEL and BayesDel scores unavailable
conservation data not assessed.

Sources

spliceai ↗

PP5 No reputable source (ClinVar, expert panel, or published literature) has classified this variant as pathogenic. The variant is absent from ClinVar. Details ▾Hide ▴

Evidence considered

Variant absent from ClinVar
no expert panel classification available.

Sources

clinvar ↗

BA1 The variant allele frequency in gnomAD v4.1 (0.00018%) is far below the 1% BA1 threshold. Details ▾Hide ▴

Evidence considered

gnomAD v4.1 AF = 0.00018% (1/570
831 alleles).

Sources

gnomad_v4 ↗

BS1 The variant allele frequency in gnomAD v4.1 (0.00018%) is far below the 0.3% BS1 threshold and is not greater than expected for an EZHIP-associated disorder. Details ▾Hide ▴

Evidence considered

gnomAD v4.1 AF = 0.00018% (1/570
831 alleles).

Sources

gnomad_v4 ↗

BP4 Only SpliceAI was available and predicts no splicing impact (max delta = 0.00). BP4 requires multiple lines of computational evidence supporting a benign effect; REVEL and BayesDel are unavailable, and conservation data were not assessed. Details ▾Hide ▴

Evidence considered

SpliceAI max delta = 0.00 — no splice impact predicted
no additional in silico scores available.

Still missing

REVEL
BayesDel
and conservation data unavailable.

Sources

spliceai ↗

BP6 No reputable source (ClinVar, expert panel, or published literature) has classified this variant as benign. The variant is absent from ClinVar. Details ▾Hide ▴

Evidence considered

Variant absent from ClinVar
no benign classification from any reputable source.

Sources

clinvar ↗

Not assessed · 12 · no assessment recorded

PS2 No de novo data with confirmed maternity and paternity are available for this variant. Details ▾Hide ▴

Still missing

No patient or family data available.

PS3 No well-established functional studies demonstrating a damaging effect have been identified for this variant. Details ▾Hide ▴

Still missing

No functional data available from literature or curated databases.

PS4 No case-control or cohort prevalence data are available; the variant is absent from ClinVar and unreported in affected individuals. Details ▾Hide ▴

Still missing

No affected-individual data available.

PM6 No de novo data (with or without confirmed parentage) are available for this variant. Details ▾Hide ▴

Still missing

No patient or family data available.

PP1 No cosegregation data with disease in multiple affected family members are available. Details ▾Hide ▴

Still missing

No family or pedigree data available.

PP4 No patient phenotype or family history data are available to assess specificity for an EZHIP-associated disorder. Details ▾Hide ▴

Still missing

No clinical phenotype data available.

BS2 A single carrier is present in gnomAD v4.1 but no phenotype data are available for this individual; cannot confirm observation in a healthy adult with full penetrance expected at an early age. Details ▾Hide ▴

Evidence considered

One heterozygous carrier in gnomAD v4.1
phenotype unknown.

Still missing

No phenotype data on the single gnomAD carrier.

Sources

gnomad_v4 ↗

BS3 No well-established functional studies demonstrating no damaging effect have been identified for this variant. Details ▾Hide ▴

Still missing

No functional data available.

BS4 No segregation data in affected families are available to assess lack of cosegregation with disease. Details ▾Hide ▴

Still missing

No family or pedigree data available.

BP2 No data are available on whether this variant has been observed in trans with a pathogenic variant in EZHIP. Details ▾Hide ▴

Still missing

No phase or trans-configuration data available.

BP5 No data are available on whether this variant has been observed in a case with an alternate molecular basis for disease. Details ▾Hide ▴

Still missing

No patient-level molecular data available.

PS5 No alternative pathogenic variant has been reported at this nucleotide position. Details ▾Hide ▴

Still missing

No data on alternative nucleotide changes at c.162.

Not applicable · 7· recorded as not applicable Show reasons ▾Hide reasons ▴

PVS1 N/ANM_203407.3:c.162C>T is a synonymous variant (p.Pro54=) and does not fall into the generic PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants. Details ▾Hide ▴

Evidence considered

Synonymous substitution with no predicted effect on splicing (SpliceAI max delta = 0.00).

Sources

pvs1_variant_assessmentpvs1_generic_framework ↗

PM3 N/APM3 requires observation in trans with a pathogenic variant for recessive disorders; no trans data available and EZHIP is on chromosome X. Details ▾Hide ▴

No further detail was recorded.

PM4 N/APM4 applies to protein-length-altering variants (in-frame indels, stop-loss); NM_203407.3:c.162C>T is a single-nucleotide synonymous substitution that does not alter protein length. Details ▾Hide ▴

No further detail was recorded.

PM5 N/ANM_203407.3:c.162C>T is a synonymous variant (p.Pro54=) producing no amino acid change; PM5 requires a novel missense change at a residue where a different pathogenic missense change has been established. Details ▾Hide ▴

Evidence considered

Synonymous variant — no amino acid change to compare.

PP2 N/ANM_203407.3:c.162C>T is a synonymous variant, not a missense change; PP2 applies only to missense variants in genes with a low rate of benign missense variation. Details ▾Hide ▴

Evidence considered

Synonymous variant — not eligible for PP2.

BP1 N/ANM_203407.3:c.162C>T is a synonymous variant, not a missense change; BP1 applies only to missense variants in genes where only truncating variants cause disease. Details ▾Hide ▴

Evidence considered

Synonymous variant — not eligible for BP1.

BP3 N/ABP3 applies to in-frame indels in repetitive regions; NM_203407.3:c.162C>T is a single-nucleotide substitution. Details ▾Hide ▴

No further detail was recorded.

Identifiers

Gene: EZHIP
Transcript: NM_203407.3
Coding (HGVS c.): NM_203407.3:c.162C>T
Protein (HGVS p.): NP_981952.1:p.(Pro54=)
GRCh38: chrX:51407178 C>T
GRCh37: chrX:51150030 C>T

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…

Exons

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Transcript span

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Strand

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Variants mapped

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Source

UCSC ncbiRefSeqCurated

All variants in EZHIP — Select a row to find it on the plot; use the link to open its page.

	Protein	Location	Classification	Link

gnomAD v4.1 1 / 570,831 alleles AF 1.75e-06 · 0 homozygotes

gnomAD v2.1 Allele count data not recorded

gnomAD-Canada v1.0 Allele count data not recorded

By genetic ancestry

gnomAD v4.1

AF 1.8e-06 · 1 / 570,831 alleles · 0 hom

European (non-Finnish)1 / 309,434

3.2e-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.

Statements

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 1.75183e-06; MAF= 0.00018%, 1/570831 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 3.23171e-06; MAF= 0.00032%, 1/309434 alleles, homozygotes = 0).

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat +50 bp

0.000

SpliceAI acceptor gainat -19 bp

0.000

SpliceAI donor lossat +172 bp

0.000

SpliceAI donor gainat +170 bp

0.000

Pangolin splice lossmagnitude shown

-0.000

Pangolin splice gain

0.000

Other predictors

REVEL: Not available
BayesDel: Not available

How the predictions were used

Evidence considered

Synonymous substitution (CCC→CCT
both encode Proline)
SpliceAI max delta = 0.00 — no splice impact predicted.

Still missing

Nucleotide conservation not explicitly assessed.

Sources

spliceai ↗

PP3 SpliceAI predicts no splicing impact (max delta = 0.00), and REVEL and BayesDel scores are unavailable for this variant. No in silico tool predicts a deleterious effect. Details ▾Hide ▴

Evidence considered

SpliceAI max delta = 0.00 (no predicted splice impact)
REVEL: not available for this genomic position
BayesDel: not available for this genomic position

Still missing

REVEL and BayesDel scores unavailable
conservation data not assessed.

Sources

spliceai ↗

Evidence considered

SpliceAI max delta = 0.00 — no splice impact predicted
no additional in silico scores available.

Still missing

REVEL
BayesDel
and conservation data unavailable.

Sources

spliceai ↗

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).

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 / 570,831 recorded alleles Open source ↗

gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗

SpliceAI Lookup Recorded maximum delta 0.000 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

gnomAD v2.1

Absent from gnomAD v2.1.

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 = 0.00).

Functional

OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.

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.