rs373948031

chr21-45990413-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Moderate BP6 BP7

The NM_001848.3(COL6A1):c.993C>T(p.Asp331=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000587 in 1,074,032 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).

• Frequency:
  • Genomes: 𝑓 0.00059 (0 hom., cov: 0)
  • Exomes 𝑓: 0.000050 (0 hom.)
• Consequence: COL6A1 NM_001848.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: -0.569

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 -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.37).
• BP6: Variant 21-45990413-C-T is Benign according to our data. Variant chr21-45990413-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 258312.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=2}.
• BP7: Synonymous conserved (PhyloP=-0.569 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL6A1	NM_001848.3	c.993C>T	p.Asp331=	synonymous_variant	13/35	ENST00000361866.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL6A1	ENST00000361866.8	c.993C>T	p.Asp331=	synonymous_variant	13/35	1	NM_001848.3	P1

Frequencies

GnomAD3 genomes AF: 0.000589 AC: 10 AN: 16968 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00157

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000713

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00262

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000117

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000836 AC: 17 AN: 203458 Hom.: 1 AF XY: 0.0000891 AC XY: 10 AN XY: 112296

Gnomad AFR exome AF: 0.000850

Gnomad AMR exome AF: 0.000115

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000893

Gnomad SAS exome AF: 0.0000392

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000105

Gnomad OTH exome AF: 0.000221

GnomAD4 exome AF: 0.0000501 AC: 53 AN: 1057032 Hom.: 0 Cov.: 49 AF XY: 0.0000465 AC XY: 24 AN XY: 516504

Gnomad4 AFR exome AF: 0.000268

Gnomad4 AMR exome AF: 0.000168

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000285

Gnomad4 SAS exome AF: 0.0000814

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000369

Gnomad4 OTH exome AF: 0.0000818

GnomAD4 genome AF: 0.000588 AC: 10 AN: 17000 Hom.: 0 Cov.: 0 AF XY: 0.000986 AC XY: 8 AN XY: 8114

Gnomad4 AFR AF: 0.00156

Gnomad4 AMR AF: 0.000709

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00260

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000117

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000862 Hom.: 0

Bravo AF: 0.000170

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Aug 17, 2015

- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Bethlem myopathy 1A Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 06, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.37
Cadd	Benign	2.3
Dann	Benign	0.93

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: rs373948031; hg19: chr21-47410327; COSMIC: COSV62613001; COSMIC: COSV62613001;