X-64917865-C-T
Variant summary
Our verdict is Pathogenic. Variant got 13 ACMG points: 14P and 1B. PM1PM2PM5PP5_Very_StrongBP4
The NM_018684.4(ZC4H2):c.593G>A(p.Arg198Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R198W) has been classified as Likely pathogenic.
Frequency
Consequence
NM_018684.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 13 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 22
GnomAD4 exome Cov.: 30
GnomAD4 genome Cov.: 22
ClinVar
Submissions by phenotype
Wieacker-Wolff syndrome Pathogenic:3
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ACMG classification criteria: PS3 supporting, PS4 strong, PM2 moderate, PM6 moderate, PP1 strong -
not provided Pathogenic:2
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Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28814648, 31206972, 28345801, 23623388, 31885220, 34322088) -
Wieacker-Wolff syndrome, female-restricted Pathogenic:1
The variant is not observed in the gnomAD v2.1.1 dataset. Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID:23623388, 28814648). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000050981). A different missense change at the same codon (p.Arg198Trp) has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000432364). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at