rs7279254

chr21-45992789-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001848.3(COL6A1):c.1314G>A(p.Thr438=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00389 in 1,601,296 control chromosomes in the GnomAD database, including 200 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.020 (107 hom., cov: 34)
  • Exomes 𝑓: 0.0022 (93 hom.)
• Consequence: COL6A1 NM_001848.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.955

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP6: Variant 21-45992789-G-A is Benign according to our data. Variant chr21-45992789-G-A is described in ClinVar as [Benign]. Clinvar id is 93809.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-45992789-G-A is described in Lovd as [Benign]. Variant chr21-45992789-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.955 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0656 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL6A1	NM_001848.3	c.1314G>A	p.Thr438=	synonymous_variant	19/35	ENST00000361866.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL6A1	ENST00000361866.8	c.1314G>A	p.Thr438=	synonymous_variant	19/35	1	NM_001848.3	P1

Frequencies

GnomAD3 genomes AF: 0.0197 AC: 2992 AN: 152202 Hom.: 104 Cov.: 34

Gnomad AFR AF: 0.0674

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00870

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000470

Gnomad OTH AF: 0.0129

GnomAD3 exomes AF: 0.00529 AC: 1198 AN: 226440 Hom.: 42 AF XY: 0.00393 AC XY: 481 AN XY: 122502

Gnomad AFR exome AF: 0.0751

Gnomad AMR exome AF: 0.00350

Gnomad ASJ exome AF: 0.000319

Gnomad EAS exome AF: 0.0000581

Gnomad SAS exome AF: 0.0000361

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000227

Gnomad OTH exome AF: 0.00268

GnomAD4 exome AF: 0.00222 AC: 3213 AN: 1448976 Hom.: 93 Cov.: 33 AF XY: 0.00192 AC XY: 1381 AN XY: 719462

Gnomad4 AFR exome AF: 0.0709

Gnomad4 AMR exome AF: 0.00418

Gnomad4 ASJ exome AF: 0.000505

Gnomad4 EAS exome AF: 0.0000508

Gnomad4 SAS exome AF: 0.000131

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000292

Gnomad4 OTH exome AF: 0.00516

GnomAD4 genome AF: 0.0198 AC: 3011 AN: 152320 Hom.: 107 Cov.: 34 AF XY: 0.0195 AC XY: 1455 AN XY: 74486

Gnomad4 AFR AF: 0.0677

Gnomad4 AMR AF: 0.00869

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000456

Gnomad4 OTH AF: 0.0128

Alfa AF: 0.0109 Hom.: 14

Bravo AF: 0.0228

Asia WGS AF: 0.00606 AC: 21 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 27, 2012	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 02, 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. -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 15, 2013	- -

Bethlem myopathy 1A Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 30, 2024

- -

Collagen 6-related myopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
Cadd	Benign	4.9
Dann	Benign	0.38
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs7279254; hg19: chr21-47412703; COSMIC: COSV105278865;