rs113066678

chr2-237375004-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_004369.4(COL6A3):c.3087C>T(p.Asp1029=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00574 in 1,613,724 control chromosomes in the GnomAD database, including 30 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0036 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0060 (29 hom.)
• Consequence: COL6A3 NM_004369.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -1.04

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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 2-237375004-G-A is Benign according to our data. Variant chr2-237375004-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 94919.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-237375004-G-A is described in Lovd as [Benign]. Variant chr2-237375004-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-1.04 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00356 (542/152130) while in subpopulation NFE AF= 0.00653 (444/68010). AF 95% confidence interval is 0.00603. There are 1 homozygotes in gnomad4. There are 221 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 3 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL6A3	NM_004369.4	c.3087C>T	p.Asp1029=	synonymous_variant	8/44	ENST00000295550.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL6A3	ENST00000295550.9	c.3087C>T	p.Asp1029=	synonymous_variant	8/44	1	NM_004369.4	P1

Frequencies

GnomAD3 genomes AF: 0.00357 AC: 542 AN: 152012 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000821

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00190

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.000775

Gnomad SAS AF: 0.00332

Gnomad FIN AF: 0.000568

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00653

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00357 AC: 884 AN: 247916 Hom.: 3 AF XY: 0.00364 AC XY: 489 AN XY: 134498

Gnomad AFR exome AF: 0.000747

Gnomad AMR exome AF: 0.00171

Gnomad ASJ exome AF: 0.000797

Gnomad EAS exome AF: 0.000219

Gnomad SAS exome AF: 0.00356

Gnomad FIN exome AF: 0.00121

Gnomad NFE exome AF: 0.00582

Gnomad OTH exome AF: 0.00344

GnomAD4 exome AF: 0.00596 AC: 8718 AN: 1461594 Hom.: 29 Cov.: 33 AF XY: 0.00585 AC XY: 4251 AN XY: 727088

Gnomad4 AFR exome AF: 0.000836

Gnomad4 AMR exome AF: 0.00192

Gnomad4 ASJ exome AF: 0.000995

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.00352

Gnomad4 FIN exome AF: 0.00107

Gnomad4 NFE exome AF: 0.00704

Gnomad4 OTH exome AF: 0.00619

GnomAD4 genome AF: 0.00356 AC: 542 AN: 152130 Hom.: 1 Cov.: 32 AF XY: 0.00297 AC XY: 221 AN XY: 74354

Gnomad4 AFR AF: 0.000819

Gnomad4 AMR AF: 0.00190

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.000777

Gnomad4 SAS AF: 0.00332

Gnomad4 FIN AF: 0.000568

Gnomad4 NFE AF: 0.00653

Gnomad4 OTH AF: 0.00332

Alfa AF: 0.00516 Hom.: 0

Bravo AF: 0.00369

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.00567

EpiControl AF: 0.00492

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	COL6A3: BP4, BP7, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 22, 2019	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Nov 05, 2012

- -

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. -

Bethlem myopathy 1A Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

COL6A3-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 14, 2023

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
Cadd	Benign	0.31
Dann	Benign	0.35

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: rs113066678; hg19: chr2-238283647;