About EZHIP
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
EZHIP c.1308C>G, p.(Asn436Lys)
Classification
Benign
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is benign. Select a step to read what it means.
Benign.A benign classification under the recorded framework.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
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: 0
Benign evidence criteria: 3
Pathogenic criteria applied · 0
No pathogenic criterion marked as applied in the recorded assessment.
Benign criteria applied · 3
BA1Stand alone
BA1 · stand alone
Allele frequency exceeds 1% in gnomAD v4.1. East Asian subpopulation AF is 1.182% (363/30706 alleles) with 3 homozygous individuals. grpmax FAF is 1.082%. On chromosome X, the observation of 3 homozygotes in a general population database provides strong evidence that this is a benign polymorphism rather than a disease-causing variant.
BS1Strong
BS1 · strong
Allele frequency exceeds 0.3% in gnomAD. gnomAD v4.1 grpmax FAF is 1.082% and EAS subpopulation AF is 1.182%, both well above the 0.3% BS1 threshold. This criterion is independently met but is encompassed by the stronger BA1 finding.
BP4Supporting
BP4 · supporting
Multiple lines of computational evidence suggest no impact on gene product. SpliceAI predicts no splicing alteration (max delta score=0.01). BayesDel score is -0.940757, strongly predicting a benign effect (threshold ≤ -0.36). REVEL is not available but the available predictors are concordant for a benign interpretation.
Recorded classification: Benign
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: BA1 stand-alone benign, BS1 strong benign, BP4 supporting benign; combination = 1 stand-alone benign + 1 strong benign + 1 supporting benign, which maps to Benign.
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
395 / 569,478 alleles
gnomAD v4.1: 395 / 569,478 alleles. Recorded AF 0.000693618. Recorded homozygote count 3.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.000288968; MAF= 0.02890%, 53/183411 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.00281365; MAF= 0.28136%, 39/13861 alleles, homozygotes = 0); grpmax FAF= 0.00211489.
gnomAD-Canada
This variant is present in gnomAD-Canada v1.0 (AF= 0.000345447008428907, 5/14474 alleles, homozygotes = 0).
SpliceAI score
0.010 maximum delta
Recorded SpliceAI maximum delta score: 0.010. Refer to the recorded PP3/BP4 rationale for interpretation.
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
For specialists
Technical detail
ACMG/AMP criteria under Not recorded, with the data and sources behind each one.
26 criteria with recorded statuses: 3 met · 20 not met · 0 not assessed · 3 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
NM_203407.3:c.1308C>G (p.Asn436Lys) in EZHIP is classified as Benign based on ACMG/AMP 2015 criteria.
BA1 (stand-alone benign): Allele frequency exceeds 1% in gnomAD v4.1, with East Asian subpopulation AF of 1.182% (363/30706 alleles) and 3 homozygous individuals observed. grpmax FAF is 1.082%. This population frequency is incompatible with a highly penetrant Mendelian disease variant.
BP4 (supporting benign): Computational predictors are concordant for a benign interpretation. SpliceAI predicts no splicing alteration (max delta=0.01). BayesDel score is -0.940757, strongly predicting benign effect.
BA1 alone is sufficient for a Benign classification under ACMG/AMP 2015 combination rules. BS1 (strong benign, AF >0.3%) and BP4 (supporting benign, in silico) provide additional supporting evidence.
No criteria match.
Met · 3
BA1 Stand aloneAllele frequency exceeds 1% in gnomAD v4.1. East Asian subpopulation AF is 1.182% (363/30706 alleles) with 3 homozygous individuals. grpmax FAF is 1.082%. On chromosome X, the observation of 3 homozygotes in a general population database provides strong evidence that this is a benign polymorphism rather than a disease-causing variant. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1: EAS AF=1.182% (363/30706
- 3 homozygotes) > 1% BA1 threshold.
- gnomAD v4.1: grpmax FAF=1.082% > 1% BA1 threshold.
- 3 homozygous individuals observed despite X-chromosome location.
Sources
BS1 StrongAllele frequency exceeds 0.3% in gnomAD. gnomAD v4.1 grpmax FAF is 1.082% and EAS subpopulation AF is 1.182%, both well above the 0.3% BS1 threshold. This criterion is independently met but is encompassed by the stronger BA1 finding. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1: EAS AF=1.182% > 0.3% BS1 threshold.
- gnomAD v4.1: grpmax FAF=1.082% > 0.3% BS1 threshold.
Sources
BP4 SupportingMultiple lines of computational evidence suggest no impact on gene product. SpliceAI predicts no splicing alteration (max delta score=0.01). BayesDel score is -0.940757, strongly predicting a benign effect (threshold ≤ -0.36). REVEL is not available but the available predictors are concordant for a benign interpretation. Details ▾Hide ▴
Evidence considered
- SpliceAI: max delta 0.01 (no splicing impact predicted).
- BayesDel: -0.940757 (strongly benign
- threshold -0.36 for benign).
Sources
spliceai ↗bayesdel
Not met · 20 · evaluated, threshold not reached
PS1 No prior established pathogenic variant at the same amino acid position (p.Asn436) is documented. ClinVar is absent for this variant; no literature identifies a pathogenic N436 substitution. Details ▾Hide ▴
Evidence considered
- ClinVar: variant absent
- no pathogenic comparator at same residue.
Sources
PS2 No de novo occurrence data available for this variant. Literature pass identified 0 PMIDs; no family-based or parent-of-origin evidence present. Details ▾Hide ▴
Evidence considered
- No de novo reports identified.
PS3 No functional studies identified for NM_203407.3:c.1308C>G or a systematically characterized range that includes position p.Asn436. Literature pass found 0 PMIDs; OncoKB reports unknown oncogenic effect without variant-specific functional data. Details ▾Hide ▴
Evidence considered
- OncoKB: unknown oncogenic effect
- no variant-specific reviewed functional evidence.
- Literature pass: 0 PMIDs across evidence sources.
Sources
PS4 No case-control or prevalence data comparing affected versus general population for this variant. No affected cohort data available. Details ▾Hide ▴
Evidence considered
- No case-control or prevalence data available.
PM1 Residue p.Asn436 is not located in a statistically significant mutational hotspot per cancerhotspots.org. While EZHIP is a functionally characterized PRC2 inhibitory protein, no domain-level evidence maps residue N436 to a critical functional domain from the available data, and no CSPEC/VCEP framework defines domain boundaries for this gene. Details ▾Hide ▴
Evidence considered
- Hotspots: residue not significant.
- OncoKB: gene-level context only
- no domain hotspot identified.
Sources
PM2 This variant is present in gnomAD at frequencies exceeding the 0.1% PM2 threshold. gnomAD v2.1: 53/183411 alleles (AF=0.029%), grpmax FAF=0.211%; gnomAD v4.1: 395/569478 alleles (AF=0.069%), grpmax FAF=1.082%. The grpmax FAF in both versions exceeds 0.1%, precluding PM2 application. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: grpmax FAF 0.211% > 0.1% PM2 threshold.
- gnomAD v4.1: grpmax FAF 1.082% > 0.1% PM2 threshold.
Sources
PM5 No same-residue pathogenic comparator variants identified in ClinVar. PM5 candidate search returned 0 candidates at residue p.Asn436. Classic same-residue PM5 semantics could not be confirmed. Details ▾Hide ▴
Evidence considered
- PM5 candidates: 0 candidates at same residue.
- ClinVar: no submissions at this position.
Sources
pm5_candidatesclinvar ↗
PM6 No confirmed de novo occurrence data available. Literature pass identified 0 PMIDs; no parent-of-origin testing or de novo confirmation reported. Details ▾Hide ▴
Evidence considered
- No de novo reports identified.
PP1 No cosegregation data available. No family studies or linkage analysis reported for this variant. Details ▾Hide ▴
Evidence considered
- No cosegregation data available.
PP2 Without gene-specific metrics or a CSPEC/VCEP framework defining a low benign missense rate for EZHIP, PP2 cannot be reliably applied under generic ACMG/AMP rules. HCI prior score is not available for this gene. Details ▾Hide ▴
Evidence considered
- No gene-specific missense constraint data available
- HCI prior not supported for EZHIP.
PP3 Computational evidence does not support a deleterious effect. SpliceAI predicts no splicing impact (max delta=0.01). BayesDel score is -0.940757, strongly benign (threshold ≤ -0.36). REVEL is not available for this variant. In silico predictors favor a benign interpretation. Details ▾Hide ▴
Evidence considered
- SpliceAI: max delta 0.01 (no splice impact).
- BayesDel: -0.940757 (strongly benign prediction).
- REVEL: not available.
Sources
spliceai ↗bayesdel
PP4 No clinical phenotype data provided in the case files. Without patient phenotype specificity information, PP4 cannot be applied. Details ▾Hide ▴
Evidence considered
- No patient phenotype data available for specificity assessment.
PP5 This variant is absent from ClinVar. No reputable source has classified this variant as pathogenic. Details ▾Hide ▴
Evidence considered
- ClinVar: variant absent
- no pathogenic classifications from any submitter.
Sources
BS2 While the variant is observed in population controls at frequencies exceeding 1%, BS2 requires observation in a healthy adult individual for a disorder with full penetrance expected at an early age. No specific disease-penetrance context or healthy control confirmation data is available. Details ▾Hide ▴
Evidence considered
- No disease-penetrance context or healthy adult observation data available.
BS3 No well-established functional studies demonstrate no damaging effect on gene product for this variant. BayesDel benign prediction is computational (BP4 territory), not functional evidence. Details ▾Hide ▴
Evidence considered
- No functional studies available for this variant.
BS4 No segregation data available. No family studies demonstrating lack of cosegregation with disease. Details ▾Hide ▴
Evidence considered
- No segregation data available.
BP1 No evidence that disease in EZHIP is caused exclusively by an alternative truncating mechanism such that missense variants are unlikely to be pathogenic. BP1 requires a gene where only truncating variants cause disease. Details ▾Hide ▴
Evidence considered
- No evidence that EZHIP-related disease is exclusively caused by truncating variants.
BP5 No alternative molecular basis for disease has been documented in this case. BP5 requires a specific alternative cause to be identified. Details ▾Hide ▴
Evidence considered
- No alternative molecular basis documented.
BP6 This variant is absent from ClinVar. No reputable source has classified this variant as benign. Details ▾Hide ▴
Evidence considered
- ClinVar: variant absent
- no benign classifications from any submitter.
Sources
PS5 No experimental evidence for a different amino acid change at the same position (p.Asn436) producing a pathogenic effect. No literature or ClinVar data identifies an alternative pathogenic substitution at this residue. Details ▾Hide ▴
Evidence considered
- ClinVar: no submissions at this position
- no alternative pathogenic substitutions identified.
Sources
Not applicable · 3· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AMissense variant (c.1308C>G, p.Asn436Lys); does not fall into null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants per ClinGen SVI PVS1 framework (PMC6185798). Details ▾Hide ▴
Evidence considered
- PVS1 variant assessment confirms bucket='other'
- apply_generic_pvs1_framework=false
- missense substitution is not a PVS1-eligible null variant.
Sources
pvs1_generic_framework ↗pvs1_variant_assessment
BP2 N/ANo data on in trans observation with a pathogenic variant in a recessive disorder. EZHIP is on chromosome X and no recessive inheritance model has been established for this gene. Details ▾Hide ▴
Evidence considered
- No trans observation data available.
BP7 N/ASynonymous variant criterion. NM_203407.3:c.1308C>G is a missense variant (p.Asn436Lys), not a synonymous or intronic variant. Details ▾Hide ▴
Evidence considered
- Variant is missense (p.Asn436Lys)
- not synonymous.
Identifiers
- Gene
- EZHIP
- Transcript
- NM_203407.3
- Coding (HGVS c.)
- NM_203407.3:c.1308C>G
- Protein (HGVS p.)
- NP_981952.1:p.(Asn436Lys)
- GRCh38
- chrX:51408324 C>G
- GRCh37
- chrX:51151176 C>G
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
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
395 / 569,478 alleles
AF 0.000694 · 3 homozygotes · FAF 0.0108
gnomAD v2.1
53 / 183,411 alleles
AF 0.000289 · 0 homozygotes · FAF 0.00211
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 0.00069 · 395 / 569,478 alleles · 3 hom · FAF 0.011
| East Asian363 / 30,706 | 0.0123 hom |
| Remaining individuals9 / 26,444 | 0.00034 |
| Middle Eastern1 / 3,249 | 0.00031 |
| South Asian8 / 44,794 | 0.00018 |
| Admixed American3 / 45,051 | 6.7e-05 |
| European (non-Finnish)9 / 309,297 | 2.9e-05 |
| African/African American1 / 44,838 | 2.2e-05 |
| European (Finnish)1 / 46,363 | 2.2e-05 |
0 alternate alleles recorded in 2 other groups: Amish, Ashkenazi Jewish.
gnomAD v2.1
AF 0.00029 · 53 / 183,411 alleles · 0 hom · FAF 0.0021
| East Asian39 / 13,861 | 0.0028 |
| Remaining individuals3 / 4,534 | 0.00066 |
| South Asian4 / 19,072 | 0.00021 |
| African/African American1 / 13,150 | 7.6e-05 |
| European (non-Finnish)5 / 81,871 | 6.1e-05 |
| Admixed American1 / 27,428 | 3.6e-05 |
0 alternate alleles recorded in 2 other groups: Ashkenazi Jewish, European (Finnish).
gnomAD-Canada
AF not recorded · ? / ? alleles
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 0.000693618; MAF= 0.06936%, 395/569478 alleles, homozygotes = 3) and has highest observed frequency in the East Asian population (AF= 0.0118218; MAF= 1.18218%, 363/30706 alleles, homozygotes = 3); grpmax FAF= 0.0108199.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.000288968; MAF= 0.02890%, 53/183411 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.00281365; MAF= 0.28136%, 39/13861 alleles, homozygotes = 0); grpmax FAF= 0.00211489.
gnomAD-Canada
This variant is present in gnomAD-Canada v1.0 (AF= 0.000345447008428907, 5/14474 alleles, homozygotes = 0).
SpliceAI and Pangolin
Other predictors
- REVEL
- Not available
- BayesDel
- -0.941
How the predictions were used
BP4 SupportingMultiple lines of computational evidence suggest no impact on gene product. SpliceAI predicts no splicing alteration (max delta score=0.01). BayesDel score is -0.940757, strongly predicting a benign effect (threshold ≤ -0.36). REVEL is not available but the available predictors are concordant for a benign interpretation. Details ▾Hide ▴
Evidence considered
- SpliceAI: max delta 0.01 (no splicing impact predicted).
- BayesDel: -0.940757 (strongly benign
- threshold -0.36 for benign).
Sources
spliceai ↗bayesdel
PP3 Computational evidence does not support a deleterious effect. SpliceAI predicts no splicing impact (max delta=0.01). BayesDel score is -0.940757, strongly benign (threshold ≤ -0.36). REVEL is not available for this variant. In silico predictors favor a benign interpretation. Details ▾Hide ▴
Evidence considered
- SpliceAI: max delta 0.01 (no splice impact).
- BayesDel: -0.940757 (strongly benign prediction).
- REVEL: not available.
Sources
spliceai ↗bayesdel
BP7 N/ASynonymous variant criterion. NM_203407.3:c.1308C>G is a missense variant (p.Asn436Lys), not a synonymous or intronic variant. Details ▾Hide ▴
Evidence considered
- Variant is missense (p.Asn436Lys)
- not synonymous.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). BayesDel score = -0.940757.
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
395 / 569,478 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
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/?term=NM_203407.3%3Ac.1308C%3EG
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/X-51151176-C-G?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chrX-51408324-C-G?dataset=gnomad_r4
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/X-51408324-C-G
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_203407.3%3Ac.1308…
- OncoKB ↗www.oncokb.org/gene/EZHIP/N436K
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=EZHIP+c.1308C%3EG
- Cancer hotspots ↗www.cancerhotspots.org/
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= 0.000693618; MAF= 0.06936%, 395/569478 alleles, homozygotes = 3) and has highest observed frequency in the East Asian population (AF= 0.0118218; MAF= 1.18218%, 363/30706 alleles, homozygotes = 3); grpmax FAF= 0.0108199.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.000288968; MAF= 0.02890%, 53/183411 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.00281365; MAF= 0.28136%, 39/13861 alleles, homozygotes = 0); grpmax FAF= 0.00211489.
gnomAD-Canada
This variant is present in gnomAD-Canada v1.0 (AF= 0.000345447008428907, 5/14474 alleles, homozygotes = 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 = -0.940757.
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.