rs769795690

chr21-46003837-G-Achr21-46003837-G-Tchr21-46003837-G-C

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP4

The NM_001848.3(COL6A1):c.2911G>A(p.Val971Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000318 in 1,602,382 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V971L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 34)
  • Exomes 𝑓: 0.000030 (0 hom.)
• Consequence: COL6A1 NM_001848.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 5.32

Genes affected

COL6A1 (HGNC:2211): (collagen type VI alpha 1 chain) The collagens are a superfamily of proteins that play a role in maintaining the integrity of various tissues. Collagens are extracellular matrix proteins and have a triple-helical domain as their common structural element. Collagen VI is a major structural component of microfibrils. The basic structural unit of collagen VI is a heterotrimer of the alpha1(VI), alpha2(VI), and alpha3(VI) chains. The alpha2(VI) and alpha3(VI) chains are encoded by the COL6A2 and COL6A3 genes, respectively. The protein encoded by this gene is the alpha 1 subunit of type VI collagen (alpha1(VI) chain). Mutations in the genes that code for the collagen VI subunits result in the autosomal dominant disorder, Bethlem myopathy. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_benign. Variant got -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.3151158).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL6A1	NM_001848.3	c.2911G>A	p.Val971Met	missense_variant	35/35	ENST00000361866.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL6A1	ENST00000361866.8	c.2911G>A	p.Val971Met	missense_variant	35/35	1	NM_001848.3	P1

Frequencies

GnomAD3 genomes AF: 0.0000525 AC: 8 AN: 152244 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.0000448 AC: 11 AN: 245304 Hom.: 0 AF XY: 0.0000450 AC XY: 6 AN XY: 133470

Gnomad AFR exome AF: 0.0000637

Gnomad AMR exome AF: 0.000262

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000331

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000297 AC: 43 AN: 1450138 Hom.: 0 Cov.: 34 AF XY: 0.0000306 AC XY: 22 AN XY: 719146

Gnomad4 AFR exome AF: 0.0000904

Gnomad4 AMR exome AF: 0.000270

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000698

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000145

Gnomad4 OTH exome AF: 0.0000836

GnomAD4 genome AF: 0.0000525 AC: 8 AN: 152244 Hom.: 0 Cov.: 34 AF XY: 0.0000672 AC XY: 5 AN XY: 74372

Gnomad4 AFR AF: 0.0000965

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.0000985 Hom.: 0

Bravo AF: 0.0000642

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Bethlem myopathy 1A Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	Mar 05, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Aug 23, 2023	- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Jul 28, 2020

- -

Ullrich congenital muscular dystrophy 1A Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Mar 05, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.12
Cadd	Benign	23
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.67	D;T
Eigen	Benign	-0.076
Eigen_PC	Benign	-0.061
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.74	T;T
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.32	T;T
MetaSVM	Uncertain	-0.20	T
MutationAssessor	Uncertain	2.7	M;.
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-2.5	N;.
REVEL	Uncertain	0.46
Sift	Uncertain	0.0020	D;.
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.68	P;.
Vest4		0.27
MVP		0.76
MPC		0.84
ClinPred		0.17	T
GERP RS		2.0
Varity_R		0.17
gMVP		0.50

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: rs769795690; hg19: chr21-47423751;