chr7-92494537-C-T
Variant summary
Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PP3_Moderate
The NM_000466.3(PEX1):c.2876G>A(p.Arg959Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000248 in 1,613,736 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R959G) has been classified as Uncertain significance.
Frequency
Consequence
NM_000466.3 missense
Scores
Clinical Significance
Conservation
Publications
- familial isolated dilated cardiomyopathyInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- dilated cardiomyopathyInheritance: AR Classification: LIMITED Submitted by: ClinGen
- dilated cardiomyopathy 2BInheritance: AR Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
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ACMG classification
Our verdict: Uncertain_significance. The variant received 2 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000723 AC: 11AN: 152134Hom.: 0 Cov.: 32 show subpopulations
GnomAD2 exomes AF: 0.0000438 AC: 11AN: 251342 AF XY: 0.0000294 show subpopulations
GnomAD4 exome AF: 0.0000198 AC: 29AN: 1461602Hom.: 0 Cov.: 30 AF XY: 0.0000248 AC XY: 18AN XY: 727128 show subpopulations
GnomAD4 genome AF: 0.0000723 AC: 11AN: 152134Hom.: 0 Cov.: 32 AF XY: 0.0000673 AC XY: 5AN XY: 74298 show subpopulations
ClinVar
Submissions by phenotype
not provided Uncertain:2
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: 31374812) -
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Zellweger spectrum disorders Uncertain:1
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 959 of the PEX1 protein (p.Arg959Gln). This variant is present in population databases (rs773206107, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with PEX1-related conditions. ClinVar contains an entry for this variant (Variation ID: 593681). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PEX1 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at