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rs797045479

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_004369.4(COL6A3):​c.6181C>T​(p.Arg2061Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,834 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 Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

COL6A3
NM_004369.4 stop_gained

Scores

3
3
1

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:2

Conservation

PhyloP100: 3.11
Variant links:
Genes affected
COL6A3 (HGNC:2213): (collagen type VI alpha 3 chain) This gene encodes the alpha-3 chain, one of the three alpha chains of type VI collagen, a beaded filament collagen found in most connective tissues. The alpha-3 chain of type VI collagen is much larger than the alpha-1 and -2 chains. This difference in size is largely due to an increase in the number of subdomains, similar to von Willebrand Factor type A domains, that are found in the amino terminal globular domain of all the alpha chains. These domains have been shown to bind extracellular matrix proteins, an interaction that explains the importance of this collagen in organizing matrix components. Mutations in the type VI collagen genes are associated with Bethlem myopathy, a rare autosomal dominant proximal myopathy with early childhood onset. Mutations in this gene are also a cause of Ullrich congenital muscular dystrophy, also referred to as Ullrich scleroatonic muscular dystrophy, an autosomal recessive congenital myopathy that is more severe than Bethlem myopathy. Multiple transcript variants have been identified, but the full-length nature of only some of these variants has been described. [provided by RefSeq, Jun 2009]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 2-237361150-G-A is Pathogenic according to our data. Variant chr2-237361150-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 210752.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-237361150-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
COL6A3NM_004369.4 linkuse as main transcriptc.6181C>T p.Arg2061Ter stop_gained 16/44 ENST00000295550.9
COL6A3NM_057167.4 linkuse as main transcriptc.5563C>T p.Arg1855Ter stop_gained 15/43
COL6A3NM_057166.5 linkuse as main transcriptc.4360C>T p.Arg1454Ter stop_gained 13/41

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
COL6A3ENST00000295550.9 linkuse as main transcriptc.6181C>T p.Arg2061Ter stop_gained 16/441 NM_004369.4 P1P12111-1
COL6A3ENST00000472056.5 linkuse as main transcriptc.4360C>T p.Arg1454Ter stop_gained 13/411 P12111-4
COL6A3ENST00000353578.9 linkuse as main transcriptc.5563C>T p.Arg1855Ter stop_gained 15/435 P12111-2

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000342
AC:
5
AN:
1461834
Hom.:
0
Cov.:
31
AF XY:
0.00000275
AC XY:
2
AN XY:
727222
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.0000374
Gnomad4 NFE exome
AF:
0.00000270
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingRevvity Omics, RevvityMar 28, 2023- -
Myopathy Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingGenetic Services Laboratory, University of ChicagoApr 28, 2014- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.58
D
BayesDel_noAF
Pathogenic
0.60
CADD
Pathogenic
43
DANN
Uncertain
1.0
Eigen
Pathogenic
0.76
Eigen_PC
Uncertain
0.62
FATHMM_MKL
Uncertain
0.96
D
MutationTaster
Benign
1.0
A;A;A;A;A;A
Vest4
0.85
GERP RS
5.2

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs797045479; hg19: chr2-238269793; API