Classification rationale

PM2 BP7 VUS

EZHIP c.162C>T

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).¹ BP7 (supporting benign) is met: the variant is synonymous and SpliceAI predicts no splicing impact.² PM2 (supporting) is met: the variant is present at 0.00018% in gnomAD v4.1, below the 0.1% threshold.³ 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).⁴

PM2 + BP7 → VUS

1 spliceai ↗gnomad_v4 ↗

2 spliceai ↗

3 gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

4 generic_acmg_combination_rules

Gene diagram · NM_203407.3 · variants mapped to exon structure

EZHIP NM_203407.3

Fetching transcript structure from UCSC…

Applied criteria · 2 applied · 19 assessed

Applied · 2

Strength Supporting Moderate Strong Very strong

✓

PM2 supporting Pathogenic

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.

gnomAD v4.1: AF = 1.75e-06 (1/570831 alleles0 homozygotes)

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

✓

BP7 supporting Benign

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.

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

spliceai ↗

Assessed · not applied

Pathogenic

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.

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

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

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

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.

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

PP1 No cosegregation data with disease in multiple affected family members are available.

PP3 SpliceAI predicts no splicing impact (max delta = 0.00), and REVEL and BayesDel scores are unavailable for this variant.

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

PP5 No reputable source (ClinVar, expert panel, or published literature) has classified this variant as pathogenic.

Benign

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

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.

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.

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

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

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

BP4 Only SpliceAI was available and predicts no splicing impact (max delta = 0.00).

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

BP6 No reputable source (ClinVar, expert panel, or published literature) has classified this variant as benign.

N/A · 7 PVS1 · PM3 · PM4 · PM5 · PP2 · BP1 · BP3

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

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).

v2.1

Absent from gnomAD v2.1.

🇨🇦 CA

Absent from gnomAD-Canada v1.0.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.00018% · 1 / 570,831
0 hom

European (non-Finnish)

1 / 309,434

0.00032%

+ 9 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)

gnomAD v2.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD Canada 🇨🇦

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant is absent from ClinVar.

ClinVar ↗

In silico

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

SpliceAI ↗

Functional Unknown Oncogenic Effect

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

OncoKB ↗

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.

COSMIC ↗ Hotspots ↗

Sources & reference links

8Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots

Re-run this variant?