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.1 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.2 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.3
EZHIP
Final classification
Benign
EZHIP c.1308C>G · p.Asn436Lys
EZHIP
NM_203407.3:c.1308C>G (p.Asn436Lys) in EZHIP is classified as Benign based on ACMG/AMP 2015 criteria.
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.
Classification rationale
BA1BS1BP4
Benign
EZHIP c.1308C>G
BA1 + BS1 + BP4
→
Benign
Gene diagram
· NM_203407.3 · variants mapped to exon structure
EZHIP
NM_203407.3
Fetching transcript structure from UCSC…
Applied criteria · 3 applied · 19 assessed
Applied · 3
Strength
Supporting
Moderate
Strong
Very strong
✓
BA1
stand-alone
Benign
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.
gnomAD v4.1: EAS AF=1.182% (363/307063 homozygotes) > 1% BA1 threshold.gnomAD v4.1: grpmax FAF=1.082% > 1% BA1 threshold.
✓
BS1
strong
Benign
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.
gnomAD v4.1: EAS AF=1.182% > 0.3% BS1 threshold.gnomAD v4.1: grpmax FAF=1.082% > 0.3% BS1 threshold.
✓
BP4
supporting
Benign
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.
SpliceAI: max delta 0.01 (no splicing impact predicted).BayesDel: -0.940757 (strongly benignthreshold -0.36 for benign).
Assessed · not applied
Pathogenic
PS1
No prior established pathogenic variant at the same amino acid position (p.Asn436) is documented.
PS2
No de novo occurrence data available for this variant.
PS3
No functional studies identified for NM_203407.3:c.1308C>G or a systematically characterized range that includes position p.Asn436.
PS4
No case-control or prevalence data comparing affected versus general population for this variant.
PM1
Residue p.Asn436 is not located in a statistically significant mutational hotspot per cancerhotspots.org.
PM2
This variant is present in gnomAD at frequencies exceeding the 0.1% PM2 threshold.
PM5
No same-residue pathogenic comparator variants identified in ClinVar.
PM6
No confirmed de novo occurrence data available.
PP1
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.
PP3
Computational evidence does not support a deleterious effect.
PP4
No clinical phenotype data provided in the case files.
PP5
This variant is absent from ClinVar.
Benign
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.
BS3
No well-established functional studies demonstrate no damaging effect on gene product for this variant.
BS4
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.
BP5
No alternative molecular basis for disease has been documented in this case.
BP6
This variant is absent from ClinVar.
N/A · 3
PVS1 · BP2 · BP7
Research & evidence
Population frequency · supports benign
gnomAD v4.1
gnomAD v2.1
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.
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.
🇨🇦 CA
This variant is present in gnomAD-Canada v1.0 (AF= 0.000345447008428907, 5/14474 alleles, homozygotes = 0).
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.069%
· 395 / 569,478
3 hom · FAF 1.1%
3 hom · FAF 1.1%
East Asian 363 / 30,706 |
1.2% 3 hom |
Remaining individuals 9 / 26,444 |
0.034% |
Middle Eastern 1 / 3,249 |
0.031% |
South Asian 8 / 44,794 |
0.018% |
Admixed American 3 / 45,051 |
0.0067% |
European (non-Finnish) 9 / 309,297 |
0.0029% |
African/African American 1 / 44,838 |
0.0022% |
European (Finnish) 1 / 46,363 |
0.0022% |
+ 2 not observed (Amish, Ashkenazi Jewish)
gnomAD v2.1
0.029%
· 53 / 183,411
0 hom · FAF 0.21%
0 hom · FAF 0.21%
East Asian 39 / 13,861 |
0.28% |
Remaining individuals 3 / 4,534 |
0.066% |
South Asian 4 / 19,072 |
0.021% |
African/African American 1 / 13,150 |
0.0076% |
European (non-Finnish) 5 / 81,871 |
0.0061% |
Admixed American 1 / 27,428 |
0.0036% |
+ 2 not observed (Ashkenazi Jewish, European (Finnish))
gnomAD Canada 🇨🇦
0.035%
· 5 / 14,474
0 hom · FAF 0.036%
0 hom · FAF 0.036%
South Asian 2 / 994 |
0.2% |
Latino/Admixed American 1 / 646 |
0.15% |
European (non-Finnish) 2 / 9,402 |
0.021% |
+ 6 not observed (African/African American, Ashkenazi Jewish, East Asian, European (Finnish), Middle Eastern, Remaining individuals)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). BayesDel score = -0.940757.
Functional
Unknown Oncogenic Effect
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
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links