rs77632596

Variant names:

• chr2-237366926-T-A
• NM_004369.4:c.5261A>T

Your query was ambiguous. Multiple possible variants found:

• chr2-237366926-T-A
• chr2-237366926-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_004369.4(COL6A3):​c.5261A>T​(p.Lys1754Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K1754R) has been classified as Benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: COL6A3 NM_004369.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.293

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 4 ACMG points.

• PM1: In a domain VWFA 9 (size 173) in uniprot entity CO6A3_HUMAN there are 7 pathogenic changes around while only 2 benign (78%) in NM_004369.4
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL6A3	NM_004369.4	c.5261A>T	p.Lys1754Met	missense_variant	Exon 11 of 44	ENST00000295550.9	NP_004360.2
COL6A3	NM_057167.4	c.4643A>T	p.Lys1548Met	missense_variant	Exon 10 of 43		NP_476508.2
COL6A3	NM_057166.5	c.3440A>T	p.Lys1147Met	missense_variant	Exon 8 of 41		NP_476507.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL6A3	ENST00000295550.9	c.5261A>T	p.Lys1754Met	missense_variant	Exon 11 of 44	1	NM_004369.4	ENSP00000295550.4
COL6A3	ENST00000472056.5	c.3440A>T	p.Lys1147Met	missense_variant	Exon 8 of 41	1		ENSP00000418285.1
COL6A3	ENST00000353578.9	c.4643A>T	p.Lys1548Met	missense_variant	Exon 10 of 43	5		ENSP00000315873.4
COL6A3	ENST00000684597.1	c.*177A>T		downstream_gene_variant				ENSP00000508021.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Jan 17, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.5261A>T (p.K1754M) alteration is located in exon 11 (coding exon 10) of the COL6A3 gene. This alteration results from a A to T substitution at nucleotide position 5261, causing the lysine (K) at amino acid position 1754 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Uncertain	0.067	T
BayesDel_noAF	Benign	-0.14
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.29	.;T;.;T;.
Eigen	Benign	0.15
Eigen_PC	Benign	0.0092
FATHMM_MKL	Benign	0.27	N
LIST_S2	Uncertain	0.87	D;D;D;D;.
M_CAP	Uncertain	0.28	D
MetaRNN	Uncertain	0.58	D;D;D;D;D
MetaSVM	Uncertain	-0.20	T
MutationAssessor	Uncertain	2.7	.;M;.;.;.
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-2.0	N;N;N;.;N
REVEL	Uncertain	0.57
Sift	Benign	0.094	T;T;T;.;T
Sift4G	Pathogenic	0.0	D;D;D;D;D
Polyphen		1.0	D;D;.;.;D
Vest4		0.53
MutPred		0.64		.;Loss of methylation at K1754 (P = 0.014);.;.;.;
MVP		0.83
MPC		0.75
ClinPred		0.68	D
GERP RS		1.8
Varity_R		0.41
gMVP		0.76

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-238275569;