3-179416495-T-C
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PP3_ModeratePP5_Moderate
The NM_021629.4(GNB4):c.265A>G(p.Lys89Glu) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K89Q) has been classified as Uncertain significance.
Frequency
Consequence
NM_021629.4 missense, splice_region
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GNB4 | NM_021629.4 | c.265A>G | p.Lys89Glu | missense_variant, splice_region_variant | 5/10 | ENST00000232564.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GNB4 | ENST00000232564.8 | c.265A>G | p.Lys89Glu | missense_variant, splice_region_variant | 5/10 | 1 | NM_021629.4 | P1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 22
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Charcot-Marie-Tooth disease dominant intermediate F Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 18, 2022 | For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects GNB4 function (PMID: 23434117). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 41941). This missense change has been observed in individual(s) with Charcot-Marie-Tooth disease (PMID: 23434117, 31211173, 34071515). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 89 of the GNB4 protein (p.Lys89Glu). - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Mar 07, 2013 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at