rs112896869

Variant names:

• chr2-237381423-G-A
• rs112896869
• NM_004369.4:c.1389C>T

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.1389C>T​(p.Ala463Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0164 in 1,612,866 control chromosomes in the GnomAD database, including 269 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (19 hom., cov: 33)
  • Exomes 𝑓: 0.017 (250 hom.)
• Consequence: COL6A3 NM_004369.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -1.32

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=-0.47).
• BP6: Variant 2-237381423-G-A is Benign according to our data. Variant chr2-237381423-G-A is described in ClinVar as [Benign]. Clinvar id is 94906.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-237381423-G-A is described in Lovd as [Benign]. Variant chr2-237381423-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-1.32 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0118 (1795/152316) while in subpopulation NFE AF= 0.0195 (1328/68028). AF 95% confidence interval is 0.0186. There are 19 homozygotes in gnomad4. There are 853 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 19 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL6A3	NM_004369.4	c.1389C>T	p.Ala463Ala	synonymous_variant	Exon 5 of 44	ENST00000295550.9	NP_004360.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL6A3	ENST00000295550.9	c.1389C>T	p.Ala463Ala	synonymous_variant	Exon 5 of 44	1	NM_004369.4	ENSP00000295550.4

Frequencies

GnomAD3 genomes AF: 0.0118 AC: 1795 AN: 152198 Hom.: 19 Cov.: 33

Gnomad AFR AF: 0.00393

Gnomad AMI AF: 0.00877

Gnomad AMR AF: 0.0138

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00373

Gnomad FIN AF: 0.00273

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0195

Gnomad OTH AF: 0.0105

GnomAD3 exomes AF: 0.0112 AC: 2805 AN: 249478 Hom.: 25 AF XY: 0.0113 AC XY: 1528 AN XY: 135120

Gnomad AFR exome AF: 0.00359

Gnomad AMR exome AF: 0.0107

Gnomad ASJ exome AF: 0.00169

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00474

Gnomad FIN exome AF: 0.00302

Gnomad NFE exome AF: 0.0183

Gnomad OTH exome AF: 0.0134

GnomAD4 exome AF: 0.0169 AC: 24659 AN: 1460550 Hom.: 250 Cov.: 32 AF XY: 0.0167 AC XY: 12108 AN XY: 726676

Gnomad4 AFR exome AF: 0.00275

Gnomad4 AMR exome AF: 0.0110

Gnomad4 ASJ exome AF: 0.00256

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00478

Gnomad4 FIN exome AF: 0.00361

Gnomad4 NFE exome AF: 0.0203

Gnomad4 OTH exome AF: 0.0139

GnomAD4 genome AF: 0.0118 AC: 1795 AN: 152316 Hom.: 19 Cov.: 33 AF XY: 0.0115 AC XY: 853 AN XY: 74484

Gnomad4 AFR AF: 0.00392

Gnomad4 AMR AF: 0.0138

Gnomad4 ASJ AF: 0.00346

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00373

Gnomad4 FIN AF: 0.00273

Gnomad4 NFE AF: 0.0195

Gnomad4 OTH AF: 0.0104

Alfa AF: 0.0146 Hom.: 8

Bravo AF: 0.0123

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.0191

EpiControl AF: 0.0182

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

May 03, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Nov 05, 2012

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:3

Nov 26, 2018

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Bethlem myopathy 1A Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Collagen 6-related myopathy Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	-0.47
CADD	Benign	6.6
DANN	Benign	0.73

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: rs112896869; hg19: chr2-238290066;