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 -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_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. Variant has been reported in ClinVar as Benign (★★).

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

  Inheritance: AR, SD, AD 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: Labcorp Genetics (formerly Invitae), Orphanet, ClinGen, Ambry Genetics, Illumina
• Ullrich congenital muscular dystrophy 1A

  Inheritance: AR, AD, SD Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 2-237324767-C-G is Benign according to our data. Variant chr2-237324767-C-G is described in ClinVar as Benign. ClinVar VariationId is 94900.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.223 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004369.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL6A3	NM_004369.4	MANE Select	c.*7G>C		3_prime_UTR	Exon 44 of 44	NP_004360.2	D9ZGF2
	COL6A3	NM_057167.4		c.*7G>C		3_prime_UTR	Exon 43 of 43	NP_476508.2	P12111-2
	COL6A3	NM_057166.5		c.*7G>C		3_prime_UTR	Exon 41 of 41	NP_476507.3	P12111-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL6A3	ENST00000295550.9	TSL:1 MANE Select	c.*7G>C		3_prime_UTR	Exon 44 of 44	ENSP00000295550.4	P12111-1
	COL6A3	ENST00000472056.5	TSL:1	c.*7G>C		3_prime_UTR	Exon 41 of 41	ENSP00000418285.1	P12111-4
	COL6A3	ENST00000353578.9	TSL:5	c.*7G>C		3_prime_UTR	Exon 43 of 43	ENSP00000315873.4	P12111-2

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	-	1	Collagen 6-related myopathy (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

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;