rs35879189

Positions:

• chr2-237336220-TGCA-T
• chr2-237336220-TGCA-TGCAGCA
• chr2-237336220-TGCA-TGCAGCAGCA

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PM4_Supporting BP6_Very_Strong BA1

The NM_004369.4(COL6A3):​c.8877_8879del​(p.Ala2960del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.108 in 1,613,878 control chromosomes in the GnomAD database, including 10,585 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.078 (626 hom., cov: 31)
  • Exomes 𝑓: 0.11 (9959 hom.)
• Consequence: COL6A3 NM_004369.4 inframe_deletion
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.80

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]

ACMG classification

Verdict is Benign. Variant got -15 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_004369.4. Strenght limited to Supporting due to length of the change: 1aa.
• BP6: Variant 2-237336220-TGCA-T is Benign according to our data. Variant chr2-237336220-TGCA-T is described in ClinVar as [Benign]. Clinvar id is 95012.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-237336220-TGCA-T is described in Lovd as [Benign]. Variant chr2-237336220-TGCA-T is described in Lovd as [Pathogenic].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.116 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL6A3	NM_004369.4	c.8877_8879del	p.Ala2960del	inframe_deletion	40/44	ENST00000295550.9	NP_004360.2
COL6A3	NM_057166.5	c.7056_7058del	p.Ala2353del	inframe_deletion	37/41		NP_476507.3
COL6A3	NM_057167.4	c.8259_8261del	p.Ala2754del	inframe_deletion	39/43		NP_476508.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL6A3	ENST00000295550.9	c.8877_8879del	p.Ala2960del	inframe_deletion	40/44	1	NM_004369.4	ENSP00000295550	P1

Frequencies

GnomAD3 genomes AF: 0.0784 AC: 11923 AN: 152138 Hom.: 626 Cov.: 31

Gnomad AFR AF: 0.0214

Gnomad AMI AF: 0.143

Gnomad AMR AF: 0.0593

Gnomad ASJ AF: 0.113

Gnomad EAS AF: 0.00942

Gnomad SAS AF: 0.0766

Gnomad FIN AF: 0.0935

Gnomad MID AF: 0.0538

Gnomad NFE AF: 0.118

Gnomad OTH AF: 0.0784

GnomAD3 exomes AF: 0.0856 AC: 21412 AN: 250082 Hom.: 1157 AF XY: 0.0887 AC XY: 12008 AN XY: 135376

Gnomad AFR exome AF: 0.0196

Gnomad AMR exome AF: 0.0459

Gnomad ASJ exome AF: 0.114

Gnomad EAS exome AF: 0.0101

Gnomad SAS exome AF: 0.0752

Gnomad FIN exome AF: 0.0984

Gnomad NFE exome AF: 0.117

Gnomad OTH exome AF: 0.0857

GnomAD4 exome AF: 0.111 AC: 162654 AN: 1461622 Hom.: 9959 AF XY: 0.110 AC XY: 80303 AN XY: 727108

Gnomad4 AFR exome AF: 0.0182

Gnomad4 AMR exome AF: 0.0490

Gnomad4 ASJ exome AF: 0.119

Gnomad4 EAS exome AF: 0.00967

Gnomad4 SAS exome AF: 0.0774

Gnomad4 FIN exome AF: 0.0981

Gnomad4 NFE exome AF: 0.124

Gnomad4 OTH exome AF: 0.102

GnomAD4 genome AF: 0.0783 AC: 11919 AN: 152256 Hom.: 626 Cov.: 31 AF XY: 0.0759 AC XY: 5650 AN XY: 74436

Gnomad4 AFR AF: 0.0213

Gnomad4 AMR AF: 0.0593

Gnomad4 ASJ AF: 0.113

Gnomad4 EAS AF: 0.00944

Gnomad4 SAS AF: 0.0769

Gnomad4 FIN AF: 0.0935

Gnomad4 NFE AF: 0.118

Gnomad4 OTH AF: 0.0771

Alfa AF: 0.0613 Hom.: 87

Bravo AF: 0.0747

Asia WGS AF: 0.0470 AC: 165 AN: 3478

EpiCase AF: 0.116

EpiControl AF: 0.115

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 31, 2012	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 05, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 14, 2017	- -

Bethlem myopathy 1A Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Collagen 6-related myopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs35879189; hg19: chr2-238244863;