rs1553544136

chr2-237334768-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_004369.4(COL6A3):c.9087T>A(p.Asp3029Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: COL6A3 NM_004369.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0390

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL6A3	NM_004369.4	c.9087T>A	p.Asp3029Glu	missense_variant	41/44	ENST00000295550.9
COL6A3	NM_057167.4	c.8469T>A	p.Asp2823Glu	missense_variant	40/43
COL6A3	NM_057166.5	c.7266T>A	p.Asp2422Glu	missense_variant	38/41

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL6A3	ENST00000295550.9	c.9087T>A	p.Asp3029Glu	missense_variant	41/44	1	NM_004369.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 60

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Bethlem myopathy 1A Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Mar 14, 2017

This sequence change replaces aspartic acid with glutamic acid at codon 3029 of the COL6A3 protein (p.Asp3029Glu). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and glutamic acid. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a COL6A3-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.42
Cadd	Benign	16
Dann	Benign	0.84
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.41
FATHMM_MKL	Benign	0.60	D
LIST_S2	Benign	0.85	T;T;T;T;.
M_CAP	Benign	0.0097	T
MetaRNN	Uncertain	0.58	D;D;D;D;D
MetaSVM	Benign	-0.96	T
MutationTaster	Benign	0.58	D;D;N;N;N;N
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-1.3	N;N;N;.;N
REVEL	Benign	0.16
Sift	Benign	0.14	T;T;T;.;T
Sift4G	Benign	0.16	T;T;T;T;T
Polyphen		0.86	P;P;.;.;P
Vest4		0.59
MutPred		0.55		.;Loss of sheet (P = 0.0817);.;.;.;
MVP		0.53
MPC		0.14
ClinPred		0.73	D
GERP RS		-3.4
Varity_R		0.098
gMVP		0.46

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs1553544136; hg19: chr2-238243411;