NM_203407.3:c.162C>T

EZHIP · NP_981952.1:p.(Pro54=) · NM_203407.3

GRCh37: chrX:51150030 C>T · GRCh38: chrX:51407178 C>T

Gene: EZHIP Transcript: NM_203407.3

Final call

VUS

PM2 supporting BP7 supporting benign

Variant details

Gene

EZHIP

Transcript

NM_203407.3

Protein

NP_981952.1:p.(Pro54=)

gnomAD AF

1.751831978291298e-06 (v4.1)

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

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).

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, so the variant is classified as Variant of Uncertain Significance.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	NM_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.	pvs1_variant_assessment pvs1_generic_framework
PS1	Not met	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.	clinvar
PS2	Not assessed	No de novo data with confirmed maternity and paternity are available for this variant.
PS3	Not assessed	No well-established functional studies demonstrating a damaging effect have been identified for this variant.
PS4	Not assessed	No case-control or cohort prevalence data are available; the variant is absent from ClinVar and unreported in affected individuals.
PS5	Not assessed	No alternative pathogenic variant has been reported at this nucleotide position.
PM1	Not met	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.
PM2	Met	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_v2 gnomad_v4 gnomad_canada
PM5	N/A	NM_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.
PM6	Not assessed	No de novo data (with or without confirmed parentage) are available for this variant.
PP1	Not assessed	No cosegregation data with disease in multiple affected family members are available.
PP2	N/A	NM_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.
PP3	Not met	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.	spliceai
PP4	Not assessed	No patient phenotype or family history data are available to assess specificity for an EZHIP-associated disorder.
PP5	Not met	No reputable source (ClinVar, expert panel, or published literature) has classified this variant as pathogenic. The variant is absent from ClinVar.	clinvar
BA1	Not met	The variant allele frequency in gnomAD v4.1 (0.00018%) is far below the 1% BA1 threshold.	gnomad_v4
BS1	Not met	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.	gnomad_v4
BS2	Not assessed	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.	gnomad_v4
BS3	Not assessed	No well-established functional studies demonstrating no damaging effect have been identified for this variant.
BS4	Not assessed	No segregation data in affected families are available to assess lack of cosegregation with disease.
BP1	N/A	NM_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.
BP2	Not assessed	No data are available on whether this variant has been observed in trans with a pathogenic variant in EZHIP.
BP3	N/A	BP3 applies to in-frame indels in repetitive regions; NM_203407.3:c.162C>T is a single-nucleotide substitution.
BP4	Not met	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.	spliceai
BP5	Not assessed	No data are available on whether this variant has been observed in a case with an alternate molecular basis for disease.
BP6	Not met	No reputable source (ClinVar, expert panel, or published literature) has classified this variant as benign. The variant is absent from ClinVar.	clinvar
BP7	Met	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.	spliceai
PM3	N/A	PM3 requires observation in trans with a pathogenic variant for recessive disorders; no trans data available and EZHIP is on chromosome X.
PM4	N/A	PM4 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.

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