rs741956

Positions:

• chr21-45986507-G-A
• chr21-45986507-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001848.3(COL6A1):​c.429-19G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.224 in 1,551,888 control chromosomes in the GnomAD database, including 42,114 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (3057 hom., cov: 32)
  • Exomes 𝑓: 0.23 (39057 hom.)
• Consequence: COL6A1 NM_001848.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -2.48

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 21-45986507-G-A is Benign according to our data. Variant chr21-45986507-G-A is described in ClinVar as [Benign]. Clinvar id is 93876.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-45986507-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.239 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL6A1	NM_001848.3	c.429-19G>A		intron_variant		ENST00000361866.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL6A1	ENST00000361866.8	c.429-19G>A		intron_variant		1	NM_001848.3	P1

Frequencies

GnomAD3 genomes AF: 0.185 AC: 28093 AN: 151974 Hom.: 3055 Cov.: 32

Gnomad AFR AF: 0.102

Gnomad AMI AF: 0.206

Gnomad AMR AF: 0.186

Gnomad ASJ AF: 0.171

Gnomad EAS AF: 0.00830

Gnomad SAS AF: 0.0966

Gnomad FIN AF: 0.272

Gnomad MID AF: 0.0981

Gnomad NFE AF: 0.242

Gnomad OTH AF: 0.178

GnomAD3 exomes AF: 0.182 AC: 29123 AN: 159964 Hom.: 3247 AF XY: 0.180 AC XY: 15238 AN XY: 84488

Gnomad AFR exome AF: 0.0976

Gnomad AMR exome AF: 0.156

Gnomad ASJ exome AF: 0.169

Gnomad EAS exome AF: 0.00567

Gnomad SAS exome AF: 0.111

Gnomad FIN exome AF: 0.270

Gnomad NFE exome AF: 0.243

Gnomad OTH exome AF: 0.189

GnomAD4 exome AF: 0.228 AC: 319313 AN: 1399796 Hom.: 39057 Cov.: 32 AF XY: 0.224 AC XY: 154871 AN XY: 690758

Gnomad4 AFR exome AF: 0.0981

Gnomad4 AMR exome AF: 0.159

Gnomad4 ASJ exome AF: 0.169

Gnomad4 EAS exome AF: 0.00618

Gnomad4 SAS exome AF: 0.110

Gnomad4 FIN exome AF: 0.265

Gnomad4 NFE exome AF: 0.252

Gnomad4 OTH exome AF: 0.204

GnomAD4 genome AF: 0.185 AC: 28105 AN: 152092 Hom.: 3057 Cov.: 32 AF XY: 0.184 AC XY: 13691 AN XY: 74336

Gnomad4 AFR AF: 0.102

Gnomad4 AMR AF: 0.186

Gnomad4 ASJ AF: 0.171

Gnomad4 EAS AF: 0.00871

Gnomad4 SAS AF: 0.0975

Gnomad4 FIN AF: 0.272

Gnomad4 NFE AF: 0.242

Gnomad4 OTH AF: 0.176

Alfa AF: 0.133 Hom.: 373

Bravo AF: 0.176

Asia WGS AF: 0.0540 AC: 190 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 09, 2012	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 05, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Bethlem myopathy 1A Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 30, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Ullrich congenital muscular dystrophy 1A Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.054
DANN	Benign	0.59

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: rs741956; hg19: chr21-47406421; COSMIC: COSV62613620; COSMIC: COSV62613620;