rs6725567

Variant names:

• chr2-237344875-C-T
• rs6725567
• NM_004369.4:c.7175-32G>A

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.7175-32G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0277 in 1,613,880 control chromosomes in the GnomAD database, including 1,843 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.067 (791 hom., cov: 32)
  • Exomes 𝑓: 0.024 (1052 hom.)
• Consequence: COL6A3 NM_004369.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.186
• Publications: 5 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=-0.82).
• BP6: Variant 2-237344875-C-T is Benign according to our data. Variant chr2-237344875-C-T is described in ClinVar as Benign. ClinVar VariationId is 94982.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.185 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.7175-32G>A		intron	N/A	NP_004360.2	D9ZGF2
	COL6A3	NM_057167.4		c.6557-32G>A		intron	N/A	NP_476508.2	P12111-2
	COL6A3	NM_057166.5		c.5354-32G>A		intron	N/A	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.7175-32G>A		intron	N/A	ENSP00000295550.4	P12111-1
	COL6A3	ENST00000472056.5	TSL:1	c.5354-32G>A		intron	N/A	ENSP00000418285.1	P12111-4
	COL6A3	ENST00000353578.9	TSL:5	c.6557-32G>A		intron	N/A	ENSP00000315873.4	P12111-2

Frequencies

GnomAD3 genomes AF: 0.0674 AC: 10246 AN: 152114 Hom.: 790 Cov.: 32

Gnomad AFR AF: 0.189

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0377

Gnomad ASJ AF: 0.0412

Gnomad EAS AF: 0.00424

Gnomad SAS AF: 0.0236

Gnomad FIN AF: 0.00754

Gnomad MID AF: 0.0633

Gnomad NFE AF: 0.0198

Gnomad OTH AF: 0.0641

GnomAD2 exomes AF: 0.0330 AC: 8259 AN: 250182 AF XY: 0.0302

Gnomad AFR exome AF: 0.200

Gnomad AMR exome AF: 0.0262

Gnomad ASJ exome AF: 0.0422

Gnomad EAS exome AF: 0.00408

Gnomad FIN exome AF: 0.00762

Gnomad NFE exome AF: 0.0219

Gnomad OTH exome AF: 0.0303

GnomAD4 exome AF: 0.0235 AC: 34378 AN: 1461648 Hom.: 1052 Cov.: 34 AF XY: 0.0231 AC XY: 16817 AN XY: 727142

African (AFR) AF: 0.200 AC: 6683 AN: 33478

American (AMR) AF: 0.0270 AC: 1209 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0429 AC: 1121 AN: 26136

East Asian (EAS) AF: 0.00181 AC: 72 AN: 39700

South Asian (SAS) AF: 0.0261 AC: 2250 AN: 86258

European-Finnish (FIN) AF: 0.00929 AC: 494 AN: 53192

Middle Eastern (MID) AF: 0.0657 AC: 379 AN: 5768

European-Non Finnish (NFE) AF: 0.0181 AC: 20126 AN: 1112000

Other (OTH) AF: 0.0338 AC: 2044 AN: 60392

GnomAD4 genome AF: 0.0674 AC: 10264 AN: 152232 Hom.: 791 Cov.: 32 AF XY: 0.0649 AC XY: 4830 AN XY: 74440

African (AFR) AF: 0.189 AC: 7832 AN: 41524

American (AMR) AF: 0.0376 AC: 575 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0412 AC: 143 AN: 3472

East Asian (EAS) AF: 0.00406 AC: 21 AN: 5178

South Asian (SAS) AF: 0.0237 AC: 114 AN: 4818

European-Finnish (FIN) AF: 0.00754 AC: 80 AN: 10616

Middle Eastern (MID) AF: 0.0612 AC: 18 AN: 294

European-Non Finnish (NFE) AF: 0.0198 AC: 1347 AN: 68008

Other (OTH) AF: 0.0634 AC: 134 AN: 2114

Alfa AF: 0.0475 Hom.: 168

Bravo AF: 0.0758

Asia WGS AF: 0.0280 AC: 96 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	4.1
DANN	Benign	0.52
PhyloP100		-0.19
PromoterAI		-0.011	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs6725567; hg19: chr2-238253518;