rs35114079

Variant names:

• chr2-237371910-G-A
• rs35114079
• NM_004369.4:c.4107C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-237371910-G-A
• chr2-237371910-G-C

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.4107C>T​(p.Ile1369Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00836 in 1,613,892 control chromosomes in the GnomAD database, including 70 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0054 (7 hom., cov: 32)
  • Exomes 𝑓: 0.0087 (63 hom.)
• Consequence: COL6A3 NM_004369.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -1.40
• 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: AD, SD, AR Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Ambry Genetics
• collagen 6-related myopathy

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

  Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
• Ullrich congenital muscular dystrophy 1A

  Inheritance: AD, SD, AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp
• dystonia 27

  Inheritance: AR Classification: STRONG, SUPPORTIVE, LIMITED, NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae), Illumina, Ambry Genetics, ClinGen, Orphanet
• 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=-0.84).
• BP6: Variant 2-237371910-G-A is Benign according to our data. Variant chr2-237371910-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 94928.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.4 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00536 (816/152118) while in subpopulation NFE AF = 0.00922 (627/67992). AF 95% confidence interval is 0.00862. There are 7 homozygotes in GnomAd4. There are 358 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 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.4107C>T	p.Ile1369Ile	synonymous	Exon 9 of 44	NP_004360.2
	COL6A3	NM_057167.4		c.3489C>T	p.Ile1163Ile	synonymous	Exon 8 of 43	NP_476508.2
	COL6A3	NM_057166.5		c.2286C>T	p.Ile762Ile	synonymous	Exon 6 of 41	NP_476507.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL6A3	ENST00000295550.9	TSL:1 MANE Select	c.4107C>T	p.Ile1369Ile	synonymous	Exon 9 of 44	ENSP00000295550.4
	COL6A3	ENST00000472056.5	TSL:1	c.2286C>T	p.Ile762Ile	synonymous	Exon 6 of 41	ENSP00000418285.1
	COL6A3	ENST00000392004.7	TSL:1	c.3489C>T	p.Ile1163Ile	synonymous	Exon 8 of 8	ENSP00000375861.3

Frequencies

GnomAD3 genomes AF: 0.00537 AC: 817 AN: 152000 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.00162

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00373

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.00250

Gnomad FIN AF: 0.00302

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00922

Gnomad OTH AF: 0.00669

GnomAD2 exomes AF: 0.00533 AC: 1340 AN: 251300 AF XY: 0.00545

Gnomad AFR exome AF: 0.00154

Gnomad AMR exome AF: 0.00318

Gnomad ASJ exome AF: 0.00278

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00325

Gnomad NFE exome AF: 0.00864

Gnomad OTH exome AF: 0.00684

GnomAD4 exome AF: 0.00867 AC: 12670 AN: 1461774 Hom.: 63 Cov.: 32 AF XY: 0.00857 AC XY: 6231 AN XY: 727164

African (AFR) AF: 0.00152 AC: 51 AN: 33480

American (AMR) AF: 0.00326 AC: 146 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00283 AC: 74 AN: 26136

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

South Asian (SAS) AF: 0.00285 AC: 246 AN: 86258

European-Finnish (FIN) AF: 0.00340 AC: 181 AN: 53302

Middle Eastern (MID) AF: 0.00468 AC: 27 AN: 5768

European-Non Finnish (NFE) AF: 0.0103 AC: 11487 AN: 1112012

Other (OTH) AF: 0.00755 AC: 456 AN: 60394

GnomAD4 genome AF: 0.00536 AC: 816 AN: 152118 Hom.: 7 Cov.: 32 AF XY: 0.00481 AC XY: 358 AN XY: 74362

African (AFR) AF: 0.00161 AC: 67 AN: 41502

American (AMR) AF: 0.00373 AC: 57 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3470

East Asian (EAS) AF: 0.000195 AC: 1 AN: 5140

South Asian (SAS) AF: 0.00229 AC: 11 AN: 4798

European-Finnish (FIN) AF: 0.00302 AC: 32 AN: 10596

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00922 AC: 627 AN: 67992

Other (OTH) AF: 0.00662 AC: 14 AN: 2116

Alfa AF: 0.00645 Hom.: 1

Bravo AF: 0.00537

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00872

EpiControl AF: 0.00771

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	3	not specified (3)
-	-	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	-0.84
CADD	Benign	0.068
DANN	Benign	0.65
PhyloP100		-1.4
PromoterAI		0.0013	Neutral
Mutation Taster		=90/10	polymorphism

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: rs35114079; hg19: chr2-238280553; COSMIC: COSV55110256;