rs113074898

chr2-237368780-C-Gchr2-237368780-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_004369.4(COL6A3):c.4683G>C(p.Gln1561His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. Q1561Q) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: COL6A3 NM_004369.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.898

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.26430306).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL6A3	NM_004369.4	c.4683G>C	p.Gln1561His	missense_variant	10/44	ENST00000295550.9
COL6A3	NM_057167.4	c.4065G>C	p.Gln1355His	missense_variant	9/43
COL6A3	NM_057166.5	c.2862G>C	p.Gln954His	missense_variant	7/41

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL6A3	ENST00000295550.9	c.4683G>C	p.Gln1561His	missense_variant	10/44	1	NM_004369.4	P1
COL6A3	ENST00000472056.5	c.2862G>C	p.Gln954His	missense_variant	7/41	1
COL6A3	ENST00000353578.9	c.4065G>C	p.Gln1355His	missense_variant	9/43	5
COL6A3	ENST00000684597.1	c.117-104G>C		intron_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251468 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135914

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.077	T
BayesDel_noAF	Benign	-0.35
Cadd	Benign	15
Dann	Benign	0.90
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.65
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.84	T;T;T;T;.
M_CAP	Uncertain	0.20	D
MetaRNN	Benign	0.26	T;T;T;T;T
MetaSVM	Benign	-0.63	T
MutationTaster	Benign	1.0	N;N;N;N;N;N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-1.8	N;N;N;.;N
REVEL	Uncertain	0.33
Sift	Benign	0.042	D;D;D;.;D
Sift4G	Uncertain	0.032	D;T;D;D;D
Polyphen		0.99	D;P;.;.;D
Vest4		0.23
MutPred		0.44		.;Loss of MoRF binding (P = 0.1663);.;.;.;
MVP		0.83
MPC		0.57
ClinPred		0.20	T
GERP RS		0.66
Varity_R		0.20
gMVP		0.49

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: rs113074898; hg19: chr2-238277423;