NM_004369.4:c.4533G>T

Variant names:

• chr2-237368930-C-A
• rs2645774
• NM_004369.4:c.4533G>T

Variant summary

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

The NM_004369.4(COL6A3):​c.4533G>T​(p.Gly1511Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.227 in 1,613,952 control chromosomes in the GnomAD database, including 42,768 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.24 (4513 hom., cov: 32)
  • Exomes 𝑓: 0.23 (38255 hom.)
• Consequence: COL6A3 NM_004369.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: -5.14

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=-0.76).
• BP6: Variant 2-237368930-C-A is Benign according to our data. Variant chr2-237368930-C-A is described in ClinVar as [Benign]. Clinvar id is 94936.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-237368930-C-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-5.14 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.288 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL6A3	NM_004369.4	c.4533G>T	p.Gly1511Gly	synonymous_variant	Exon 10 of 44	ENST00000295550.9	NP_004360.2
COL6A3	NM_057167.4	c.3915G>T	p.Gly1305Gly	synonymous_variant	Exon 9 of 43		NP_476508.2
COL6A3	NM_057166.5	c.2712G>T	p.Gly904Gly	synonymous_variant	Exon 7 of 41		NP_476507.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL6A3	ENST00000295550.9	c.4533G>T	p.Gly1511Gly	synonymous_variant	Exon 10 of 44	1	NM_004369.4	ENSP00000295550.4
COL6A3	ENST00000472056.5	c.2712G>T	p.Gly904Gly	synonymous_variant	Exon 7 of 41	1		ENSP00000418285.1
COL6A3	ENST00000353578.9	c.3915G>T	p.Gly1305Gly	synonymous_variant	Exon 9 of 43	5		ENSP00000315873.4
COL6A3	ENST00000684597.1	c.116-254G>T		intron_variant	Intron 1 of 2			ENSP00000508021.1

Frequencies

GnomAD3 genomes AF: 0.241 AC: 36608 AN: 151946 Hom.: 4496 Cov.: 32

Gnomad AFR AF: 0.276

Gnomad AMI AF: 0.133

Gnomad AMR AF: 0.295

Gnomad ASJ AF: 0.218

Gnomad EAS AF: 0.254

Gnomad SAS AF: 0.253

Gnomad FIN AF: 0.190

Gnomad MID AF: 0.248

Gnomad NFE AF: 0.216

Gnomad OTH AF: 0.242

GnomAD3 exomes AF: 0.238 AC: 59940 AN: 251392 Hom.: 7418 AF XY: 0.234 AC XY: 31844 AN XY: 135880

Gnomad AFR exome AF: 0.279

Gnomad AMR exome AF: 0.321

Gnomad ASJ exome AF: 0.193

Gnomad EAS exome AF: 0.256

Gnomad SAS exome AF: 0.244

Gnomad FIN exome AF: 0.196

Gnomad NFE exome AF: 0.217

Gnomad OTH exome AF: 0.216

GnomAD4 exome AF: 0.226 AC: 330106 AN: 1461888 Hom.: 38255 Cov.: 38 AF XY: 0.225 AC XY: 163965 AN XY: 727248

Gnomad4 AFR exome AF: 0.281

Gnomad4 AMR exome AF: 0.319

Gnomad4 ASJ exome AF: 0.193

Gnomad4 EAS exome AF: 0.246

Gnomad4 SAS exome AF: 0.242

Gnomad4 FIN exome AF: 0.191

Gnomad4 NFE exome AF: 0.221

Gnomad4 OTH exome AF: 0.226

GnomAD4 genome AF: 0.241 AC: 36676 AN: 152064 Hom.: 4513 Cov.: 32 AF XY: 0.243 AC XY: 18090 AN XY: 74350

Gnomad4 AFR AF: 0.276

Gnomad4 AMR AF: 0.296

Gnomad4 ASJ AF: 0.218

Gnomad4 EAS AF: 0.255

Gnomad4 SAS AF: 0.255

Gnomad4 FIN AF: 0.190

Gnomad4 NFE AF: 0.216

Gnomad4 OTH AF: 0.245

Alfa AF: 0.199 Hom.: 1567

Bravo AF: 0.251

Asia WGS AF: 0.263 AC: 915 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:8

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 31, 2012

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 02, 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. -

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

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

- -

Aug 15, 2013

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 31, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 57% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy, Progressive Myoclonus Epilepsy and Abnormal Movements and Neurodegeneration with brain iron accumulation. Number of patients: 53. Only high quality variants are reported. -

Bethlem myopathy 1A Benign:2

Jul 30, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dystonia 27 Benign:1

Jul 30, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Collagen 6-related myopathy Benign:1

Jan 13, 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. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Ullrich congenital muscular dystrophy 1A Benign:1

Jul 30, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	1.0
DANN	Benign	0.45

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: rs2645774; hg19: chr2-238277573; COSMIC: COSV55083712; COSMIC: COSV55083712;