chr2-237371896-T-A
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 6P and 1B. PM2PP3_StrongBS1_Supporting
The NM_004369.4(COL6A3):c.4121A>T(p.Asp1374Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000775 in 1,613,478 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 Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_004369.4 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Uncertain_significance. Variant got 5 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000461 AC: 7AN: 151728Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000103 AC: 26AN: 251286Hom.: 0 AF XY: 0.0000957 AC XY: 13AN XY: 135812
GnomAD4 exome AF: 0.0000807 AC: 118AN: 1461750Hom.: 0 Cov.: 31 AF XY: 0.0000853 AC XY: 62AN XY: 727154
GnomAD4 genome AF: 0.0000461 AC: 7AN: 151728Hom.: 0 Cov.: 32 AF XY: 0.0000540 AC XY: 4AN XY: 74052
ClinVar
Submissions by phenotype
not provided Uncertain:3
- -
- -
In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Identified in heterozygous state in an individual with isolated dystonia (Zech et al., 2015); also reported in an individual with clinically suspected LGMD (Nallamilli et al., 2018); This variant is associated with the following publications: (PMID: 30564623, 26004199) -
Bethlem myopathy 1A Pathogenic:1Benign:1
- -
- -
Ullrich congenital muscular dystrophy 1A Uncertain:1
The missense variant c.4121A>T (p.Asp1374Val) in COL6A3 gene has been reported in heterozygous state in individual affected with limb-girdle muscular dystrophy (Nallamilli et al.,2018). This variant is reported with the allele frequency (0.01%) in the gnomAD and novel in 1000 genome database. It has been submitted to ClinVar with varying interpretations: Likely Pathogenic / Uncertain Significance. The amino acid Aspartic acid at position 1374 is changed to a Valine changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at