NM_004369.4:c.9123G>A

Variant names:

• chr2-237334732-C-T
• rs61729843
• NM_004369.4:c.9123G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_004369.4(COL6A3):​c.9123G>A​(p.Thr3041Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0348 in 1,614,024 control chromosomes in the GnomAD database, including 1,123 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.026 (64 hom., cov: 32)
  • Exomes 𝑓: 0.036 (1059 hom.)
• Consequence: COL6A3 NM_004369.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -2.79
• Publications: 8 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BP6: Variant 2-237334732-C-T is Benign according to our data. Variant chr2-237334732-C-T is described in ClinVar as Benign. ClinVar VariationId is 95016.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.79 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0263 (4005/152184) while in subpopulation NFE AF = 0.0393 (2672/68008). AF 95% confidence interval is 0.038. There are 64 homozygotes in GnomAd4. There are 1980 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 64 AD,AR,SD gene

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.9123G>A	p.Thr3041Thr	synonymous	Exon 41 of 44	NP_004360.2	D9ZGF2
	COL6A3	NM_057167.4		c.8505G>A	p.Thr2835Thr	synonymous	Exon 40 of 43	NP_476508.2	P12111-2
	COL6A3	NM_057166.5		c.7302G>A	p.Thr2434Thr	synonymous	Exon 38 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.9123G>A	p.Thr3041Thr	synonymous	Exon 41 of 44	ENSP00000295550.4	P12111-1
	COL6A3	ENST00000472056.5	TSL:1	c.7302G>A	p.Thr2434Thr	synonymous	Exon 38 of 41	ENSP00000418285.1	P12111-4
	COL6A3	ENST00000353578.9	TSL:5	c.8505G>A	p.Thr2835Thr	synonymous	Exon 40 of 43	ENSP00000315873.4	P12111-2

Frequencies

GnomAD3 genomes AF: 0.0263 AC: 4003 AN: 152066 Hom.: 63 Cov.: 32

Gnomad AFR AF: 0.00642

Gnomad AMI AF: 0.00989

Gnomad AMR AF: 0.0314

Gnomad ASJ AF: 0.0265

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00747

Gnomad FIN AF: 0.0377

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0393

Gnomad OTH AF: 0.0220

GnomAD2 exomes AF: 0.0260 AC: 6537 AN: 251438 AF XY: 0.0260

Gnomad AFR exome AF: 0.00634

Gnomad AMR exome AF: 0.0147

Gnomad ASJ exome AF: 0.0206

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0409

Gnomad NFE exome AF: 0.0385

Gnomad OTH exome AF: 0.0236

GnomAD4 exome AF: 0.0356 AC: 52083 AN: 1461840 Hom.: 1059 Cov.: 60 AF XY: 0.0349 AC XY: 25359 AN XY: 727226

African (AFR) AF: 0.00499 AC: 167 AN: 33480

American (AMR) AF: 0.0152 AC: 679 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0225 AC: 589 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.0105 AC: 904 AN: 86256

European-Finnish (FIN) AF: 0.0406 AC: 2170 AN: 53418

Middle Eastern (MID) AF: 0.00872 AC: 50 AN: 5732

European-Non Finnish (NFE) AF: 0.0410 AC: 45612 AN: 1112002

Other (OTH) AF: 0.0316 AC: 1910 AN: 60392

GnomAD4 genome AF: 0.0263 AC: 4005 AN: 152184 Hom.: 64 Cov.: 32 AF XY: 0.0266 AC XY: 1980 AN XY: 74410

African (AFR) AF: 0.00641 AC: 266 AN: 41530

American (AMR) AF: 0.0313 AC: 478 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.0265 AC: 92 AN: 3470

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5164

South Asian (SAS) AF: 0.00810 AC: 39 AN: 4814

European-Finnish (FIN) AF: 0.0377 AC: 400 AN: 10600

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0393 AC: 2672 AN: 68008

Other (OTH) AF: 0.0218 AC: 46 AN: 2112

Alfa AF: 0.0282 Hom.: 31

Bravo AF: 0.0246

Asia WGS AF: 0.00462 AC: 16 AN: 3478

EpiCase AF: 0.0346

EpiControl AF: 0.0374

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	2	not provided (2)
-	-	1	Bethlem myopathy 1A (1)
-	-	1	Collagen 6-related myopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	0.083
DANN	Benign	0.47
PhyloP100		-2.8
Mutation Taster		=93/7	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs61729843; hg19: chr2-238243375; COSMIC: COSV55083076; COSMIC: COSV55083076;