2-237324814-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_004369.4(COL6A3):ā€‹c.9494T>Gā€‹(p.Val3165Gly) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,232 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: not found (cov: 32)
Exomes š‘“: 6.8e-7 ( 0 hom. )

Consequence

COL6A3
NM_004369.4 missense, splice_region

Scores

19
Splicing: ADA: 0.0001900
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.325
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 Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.09407005).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
COL6A3NM_004369.4 linkuse as main transcriptc.9494T>G p.Val3165Gly missense_variant, splice_region_variant 44/44 ENST00000295550.9
COL6A3NM_057167.4 linkuse as main transcriptc.8876T>G p.Val2959Gly missense_variant, splice_region_variant 43/43
COL6A3NM_057166.5 linkuse as main transcriptc.7673T>G p.Val2558Gly missense_variant, splice_region_variant 41/41

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
COL6A3ENST00000295550.9 linkuse as main transcriptc.9494T>G p.Val3165Gly missense_variant, splice_region_variant 44/441 NM_004369.4 P1P12111-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000403
AC:
1
AN:
248064
Hom.:
0
AF XY:
0.00000745
AC XY:
1
AN XY:
134260
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000289
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461232
Hom.:
0
Cov.:
31
AF XY:
0.00000138
AC XY:
1
AN XY:
726872
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Bethlem myopathy 1A Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpApr 12, 2022This sequence change replaces valine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 3165 of the COL6A3 protein (p.Val3165Gly). This variant is present in population databases (no rsID available, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with COL6A3-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0". The glycine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect 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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.074
BayesDel_addAF
Benign
-0.24
T
BayesDel_noAF
Benign
-0.51
CADD
Benign
4.7
DANN
Benign
0.69
DEOGEN2
Benign
0.12
.;T;.;T;.
Eigen
Benign
-1.4
Eigen_PC
Benign
-1.5
FATHMM_MKL
Benign
0.043
N
LIST_S2
Benign
0.52
T;T;T;T;.
M_CAP
Benign
0.0063
T
MetaRNN
Benign
0.094
T;T;T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
0.82
.;L;.;.;.
MutationTaster
Benign
1.0
N;N;N;N;N;N
PrimateAI
Benign
0.30
T
PROVEAN
Benign
0.64
N;N;N;D;N
REVEL
Benign
0.15
Sift
Benign
0.044
D;D;D;D;D
Sift4G
Benign
0.55
T;T;T;T;T
Polyphen
0.0
B;B;.;.;B
Vest4
0.14
MutPred
0.34
.;Loss of catalytic residue at V3165 (P = 0.0365);.;.;.;
MVP
0.23
MPC
0.19
ClinPred
0.071
T
GERP RS
-9.7
Varity_R
0.15
gMVP
0.40

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.00019
dbscSNV1_RF
Benign
0.16
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: rs1409714765; hg19: chr2-238233457; API