NM_004369.4:c.*7G>C

Variant names:

• chr2-237324767-C-G
• rs4663722
• NM_004369.4:c.*7G>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004369.4(COL6A3):​c.*7G>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.113 in 1,613,246 control chromosomes in the GnomAD database, including 12,451 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.15 (2041 hom., cov: 32)
  • Exomes 𝑓: 0.11 (10410 hom.)
• Consequence: COL6A3 NM_004369.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 1.09
• Publications: 14 publications found

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]

COL6A3 Gene-Disease associations (from GenCC):

• Bethlem myopathy 1A

  Inheritance: AD, AR, SD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Ambry Genetics
• collagen 6-related myopathy

  Inheritance: AD, AR Classification: DEFINITIVE Submitted by: ClinGen
• Ullrich congenital muscular dystrophy 1C

  Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
• dystonia 27

  Inheritance: AR Classification: STRONG, SUPPORTIVE, LIMITED, NO_KNOWN Submitted by: Illumina, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics, Orphanet
• Ullrich congenital muscular dystrophy 1A

  Inheritance: AR, AD, SD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp
• Bethlem myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Ullrich congenital muscular dystrophy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.223 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL6A3	NM_004369.4	c.*7G>C		3_prime_UTR_variant	Exon 44 of 44	ENST00000295550.9	NP_004360.2
COL6A3	NM_057167.4	c.*7G>C		3_prime_UTR_variant	Exon 43 of 43		NP_476508.2
COL6A3	NM_057166.5	c.*7G>C		3_prime_UTR_variant	Exon 41 of 41		NP_476507.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL6A3	ENST00000295550.9	c.*7G>C		3_prime_UTR_variant	Exon 44 of 44	1	NM_004369.4	ENSP00000295550.4

Frequencies

GnomAD3 genomes AF: 0.148 AC: 22461 AN: 151924 Hom.: 2033 Cov.: 32

Gnomad AFR AF: 0.227

Gnomad AMI AF: 0.0747

Gnomad AMR AF: 0.170

Gnomad ASJ AF: 0.158

Gnomad EAS AF: 0.228

Gnomad SAS AF: 0.199

Gnomad FIN AF: 0.0801

Gnomad MID AF: 0.184

Gnomad NFE AF: 0.0955

Gnomad OTH AF: 0.154

GnomAD2 exomes AF: 0.145 AC: 36031 AN: 249246 AF XY: 0.140

Gnomad AFR exome AF: 0.234

Gnomad AMR exome AF: 0.211

Gnomad ASJ exome AF: 0.162

Gnomad EAS exome AF: 0.232

Gnomad FIN exome AF: 0.0785

Gnomad NFE exome AF: 0.0961

Gnomad OTH exome AF: 0.140

GnomAD4 exome AF: 0.109 AC: 159599 AN: 1461202 Hom.: 10410 Cov.: 31 AF XY: 0.111 AC XY: 80397 AN XY: 726914

African (AFR) AF: 0.234 AC: 7822 AN: 33468

American (AMR) AF: 0.206 AC: 9221 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.161 AC: 4203 AN: 26128

East Asian (EAS) AF: 0.202 AC: 8009 AN: 39682

South Asian (SAS) AF: 0.183 AC: 15787 AN: 86216

European-Finnish (FIN) AF: 0.0754 AC: 4007 AN: 53146

Middle Eastern (MID) AF: 0.191 AC: 1099 AN: 5768

European-Non Finnish (NFE) AF: 0.0913 AC: 101531 AN: 1111710

Other (OTH) AF: 0.131 AC: 7920 AN: 60372

GnomAD4 genome AF: 0.148 AC: 22493 AN: 152044 Hom.: 2041 Cov.: 32 AF XY: 0.148 AC XY: 10976 AN XY: 74306

African (AFR) AF: 0.227 AC: 9417 AN: 41438

American (AMR) AF: 0.170 AC: 2603 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.158 AC: 548 AN: 3468

East Asian (EAS) AF: 0.228 AC: 1179 AN: 5166

South Asian (SAS) AF: 0.199 AC: 958 AN: 4818

European-Finnish (FIN) AF: 0.0801 AC: 848 AN: 10590

Middle Eastern (MID) AF: 0.177 AC: 52 AN: 294

European-Non Finnish (NFE) AF: 0.0955 AC: 6494 AN: 67978

Other (OTH) AF: 0.154 AC: 326 AN: 2112

Alfa AF: 0.0783 Hom.: 121

Bravo AF: 0.156

Asia WGS AF: 0.246 AC: 855 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:10

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, 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 28% 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: 26. Only high quality variants are reported. -

-

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 02, 2017

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 25, 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. -

Aug 15, 2013

Genetic Services Laboratory, University of Chicago

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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	5.5
DANN	Benign	0.71
PhyloP100		1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4663722; hg19: chr2-238233410;