rs121912936
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_001848.3(COL6A1):āc.362A>Gā(p.Lys121Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (ā ā ).
Frequency
Genomes: not found (cov: 35)
Exomes š: 0.0 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
COL6A1
NM_001848.3 missense
NM_001848.3 missense
Scores
1
6
12
Clinical Significance
Conservation
PhyloP100: 3.05
Genes affected
COL6A1 (HGNC:2211): (collagen type VI alpha 1 chain) The collagens are a superfamily of proteins that play a role in maintaining the integrity of various tissues. Collagens are extracellular matrix proteins and have a triple-helical domain as their common structural element. Collagen VI is a major structural component of microfibrils. The basic structural unit of collagen VI is a heterotrimer of the alpha1(VI), alpha2(VI), and alpha3(VI) chains. The alpha2(VI) and alpha3(VI) chains are encoded by the COL6A2 and COL6A3 genes, respectively. The protein encoded by this gene is the alpha 1 subunit of type VI collagen (alpha1(VI) chain). Mutations in the genes that code for the collagen VI subunits result in the autosomal dominant disorder, Bethlem myopathy. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 14 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.942
PP5
?
Variant 21-45984403-A-G is Pathogenic according to our data. Variant chr21-45984403-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 17173.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-45984403-A-G is described in Lovd as [Pathogenic]. Variant chr21-45984403-A-G is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
COL6A1 | NM_001848.3 | c.362A>G | p.Lys121Arg | missense_variant | 3/35 | ENST00000361866.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
COL6A1 | ENST00000361866.8 | c.362A>G | p.Lys121Arg | missense_variant | 3/35 | 1 | NM_001848.3 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 35
GnomAD3 genomes
?
Cov.:
35
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1460338Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 726494
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
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0
AN:
1460338
Hom.:
Cov.:
33
AF XY:
AC XY:
0
AN XY:
726494
Gnomad4 AFR exome
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GnomAD4 genome ? Cov.: 35
GnomAD4 genome
?
Cov.:
35
Bravo
AF:
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Bethlem myopathy 1A Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 28, 2023 | This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 121 of the COL6A1 protein (p.Lys121Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of autosomal dominant type VI collagenopathies (PMID: 11865138, 28877744; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 17173). 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 not expected to disrupt COL6A1 protein function with a negative predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Feb 26, 2002 | - - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Aug 24, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jul 28, 2019 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Uncertain
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
T;T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T;T
M_CAP
Benign
D
MetaRNN
Pathogenic
D;D
MetaSVM
Benign
T
MutationAssessor
Benign
N;.
MutationTaster
Benign
A
PrimateAI
Uncertain
T
PROVEAN
Benign
N;.
REVEL
Uncertain
Sift
Benign
T;.
Sift4G
Benign
T;T
Polyphen
P;.
Vest4
MutPred
Loss of ubiquitination at K121 (P = 0.027);Loss of ubiquitination at K121 (P = 0.027);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DG_spliceai
Position offset: 0
Find out detailed SpliceAI scores and Pangolin per-transcript scores at