NM_203407.3:c.1379C>G

EZHIP · NP_981952.1:p.(Ser460Cys) · NM_203407.3

GRCh37: chrX:51151247 C>G · GRCh38: chrX:51408395 C>G

Gene: EZHIP Transcript: NM_203407.3

Final call

VUS

Variant details

Gene

EZHIP

Transcript

NM_203407.3

Protein

NP_981952.1:p.(Ser460Cys)

gnomAD AF

8.753578025017726e-06 (v4.1)

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

Final classification VUS: no ACMG/AMP criterion was met, so no pathogenic or benign combination rule was satisfied under the generic ACMG/AMP 2015 framework.

Final determination: With no criteria scored as met in either the pathogenic or benign direction, no generic ACMG/AMP 2015 combining rule for Pathogenic, Likely Pathogenic, Benign, or Likely Benign is satisfied, so the variant defaults to 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	Not applicable: this is a missense substitution, not a null variant class (nonsense, frameshift, or canonical splice) expected to trigger nonsense-mediated decay.	pvs1_generic_framework generic_acmg_combination_rules
PS1	Not assessed	Not assessed: no evidence was available that this exact amino acid change has been previously established as pathogenic.
PS2	Not assessed	Not assessed: no de novo occurrence in an affected proband with confirmed maternity and paternity was documented.
PS3	Not assessed	Not assessed: no validated functional assay data demonstrating an abnormal effect for this exact variant (p.Ser460Cys) was available.	oncokb
PS4	Not assessed	Not assessed: no case series or case-control comparison showing enrichment of this variant in affected individuals was available.
PM1	Not assessed	Not assessed: insufficient evidence was available to establish whether the variant falls in a mutational hotspot or critical functional domain.
PM2	Not met	Not met: the highest population allele frequency is 0.2014% (gnomAD-Canada South Asian), exceeding the <0.1% rarity threshold. Flagged for human review: this frequency rests on only 2 alleles among 993 and may be a sampling artifact.	gnomad_v2 gnomad_v4 gnomad_canada
PM3	Not assessed	Not assessed: no evidence was available that this variant is in trans with a pathogenic variant in a recessive disorder.	final_classification_framework
PM4	N/A	Not applicable: this missense substitution does not alter protein length, which PM4 requires.	pvs1_generic_framework generic_acmg_combination_rules
PM5	Not assessed	Not assessed: no evidence was available of a different pathogenic missense change at the same amino acid residue.
PM6	Not assessed	Not assessed: no presumed de novo occurrence in an affected individual was documented.
PP1	Not assessed	Not assessed: no segregation data from affected relatives were available.
PP2	Not assessed	Not assessed: insufficient evidence was available to establish EZHIP's rate of benign missense variation.
PP3	Not assessed	Not assessed: no calibrated in-silico predictor score was available for this missense variant; REVEL is unavailable at this position and BayesDel has no verified threshold.
PP4	Not assessed	Not assessed: no patient phenotype or highly specific clinical findings were provided to match against EZHIP-associated disease.
PP5	Not met	Not met: the variant is absent from ClinVar, with no expert-panel pathogenic classification on record.	clinvar
BA1	Not met	Not met: the highest population allele frequency is 0.2014%, far below the >1% BA1 threshold.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	Not met: the highest population allele frequency is 0.2014%, below the >0.3% BS1 threshold.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not met	Not met: no homozygous or hemizygous individuals carrying this variant are reported in population datasets.	gnomad_v2 gnomad_v4 gnomad_canada
BS3	Not assessed	Not assessed: no validated assay evidence of normal protein function for this variant was available.	oncokb
BS4	Not assessed	Not assessed: no unaffected carriers of the variant within affected families were documented.
BP1	Not assessed	Not assessed: insufficient evidence was available to establish whether EZHIP disease is caused only by truncating variants.
BP2	Not assessed	Not assessed: no phase-resolved evidence of the variant's arrangement relative to a pathogenic variant was available.	final_classification_framework
BP3	N/A	Not applicable: this is a missense substitution, not an in-frame indel in a repetitive region.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Not assessed	Not assessed: no calibrated in-silico predictor score was available to evaluate a benign effect.
BP5	Not assessed	Not assessed: no alternative molecular diagnosis clearly explaining the patient's phenotype was documented.
BP6	Not met	Not met: the variant is absent from ClinVar, with no expert-panel benign classification on record.	clinvar
BP7	N/A	Not applicable: this is a missense substitution, not a synonymous variant, which BP7 requires.	generic_acmg_combination_rules

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.