2-237369154-T-G

Position:

• chr2-237369154-T-G

Variant summary

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

The NM_004369.4(COL6A3):​c.4309A>C​(p.Ile1437Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,460,208 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. I1437I) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: COL6A3 NM_004369.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.59

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	Protein	UniProt
COL6A3	NM_004369.4	c.4309A>C	p.Ile1437Leu	missense_variant	10/44	ENST00000295550.9	NP_004360.2
COL6A3	NM_057167.4	c.3691A>C	p.Ile1231Leu	missense_variant	9/43		NP_476508.2
COL6A3	NM_057166.5	c.2488A>C	p.Ile830Leu	missense_variant	7/41		NP_476507.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL6A3	ENST00000295550.9	c.4309A>C	p.Ile1437Leu	missense_variant	10/44	1	NM_004369.4	ENSP00000295550.4
COL6A3	ENST00000472056.5	c.2488A>C	p.Ile830Leu	missense_variant	7/41	1		ENSP00000418285.1
COL6A3	ENST00000353578.9	c.3691A>C	p.Ile1231Leu	missense_variant	9/43	5		ENSP00000315873.4
COL6A3	ENST00000684597.1	c.116-478A>C		intron_variant				ENSP00000508021.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000808 AC: 2 AN: 247572 Hom.: 0 AF XY: 0.00000745 AC XY: 1 AN XY: 134228

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: 0.00000898

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1460208 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 726510

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: 8.99e-7

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

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

Labcorp Genetics (formerly Invitae), Labcorp

Sep 17, 2022

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. 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 COL6A3 protein function. ClinVar contains an entry for this variant (Variation ID: 1363169). This variant has not been reported in the literature in individuals affected with COL6A3-related conditions. This variant is present in population databases (rs144314743, gnomAD 0.003%). This sequence change replaces isoleucine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1437 of the COL6A3 protein (p.Ile1437Leu). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Uncertain	0.019	T
BayesDel_noAF	Benign	-0.13
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.26	.;T;.;T;.
Eigen	Benign	0.0034
Eigen_PC	Benign	0.016
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.85	D;D;T;T;.
M_CAP	Uncertain	0.18	D
MetaRNN	Uncertain	0.56	D;D;D;D;D
MetaSVM	Uncertain	-0.18	T
MutationAssessor	Benign	1.2	.;L;.;.;.
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-1.7	N;N;N;.;N
REVEL	Uncertain	0.55
Sift	Uncertain	0.0060	D;D;D;.;D
Sift4G	Uncertain	0.0020	D;D;D;D;D
Polyphen		0.91	P;P;.;.;P
Vest4		0.58
MutPred		0.51		.;Gain of sheet (P = 0.0827);.;.;.;
MVP		0.84
MPC		0.55
ClinPred		0.43	T
GERP RS		4.1
Varity_R		0.45
gMVP		0.60

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

Other links and lift over

dbSNP: rs144314743; hg19: chr2-238277797;