rs112825341

Positions:

• chr2-237364431-G-A

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2 BP4_Strong BP6 BS1

The NM_004369.4(COL6A3):​c.5839-3C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000433 in 1,610,602 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00044 (0 hom.)
• Consequence: COL6A3 NM_004369.4 splice_region, intron
• Scores: Splicing: ADA: 0.001779
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:5
• Conservation: PhyloP100: 0.174

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 -7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 2-237364431-G-A is Benign according to our data. Variant chr2-237364431-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 282789.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=3, Likely_benign=2, Benign=2}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000394 (60/152260) while in subpopulation NFE AF= 0.000544 (37/68006). AF 95% confidence interval is 0.000405. There are 0 homozygotes in gnomad4. There are 32 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL6A3	NM_004369.4	c.5839-3C>T		splice_region_variant, intron_variant		ENST00000295550.9	NP_004360.2
COL6A3	NM_057167.4	c.5221-3C>T		splice_region_variant, intron_variant			NP_476508.2
COL6A3	NM_057166.5	c.4018-3C>T		splice_region_variant, intron_variant			NP_476507.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL6A3	ENST00000295550.9	c.5839-3C>T		splice_region_variant, intron_variant		1	NM_004369.4	ENSP00000295550.4
COL6A3	ENST00000472056.5	c.4018-3C>T		splice_region_variant, intron_variant		1		ENSP00000418285.1
COL6A3	ENST00000353578.9	c.5221-3C>T		splice_region_variant, intron_variant		5		ENSP00000315873.4

Frequencies

GnomAD3 genomes AF: 0.000388 AC: 59 AN: 152142 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000754

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000544

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000386 AC: 97 AN: 251294 Hom.: 0 AF XY: 0.000478 AC XY: 65 AN XY: 135846

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000173

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.000466

Gnomad NFE exome AF: 0.000668

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000437 AC: 638 AN: 1458342 Hom.: 0 Cov.: 29 AF XY: 0.000438 AC XY: 318 AN XY: 725822

Gnomad4 AFR exome AF: 0.0000898

Gnomad4 AMR exome AF: 0.000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.000470

Gnomad4 NFE exome AF: 0.000521

Gnomad4 OTH exome AF: 0.000216

GnomAD4 genome AF: 0.000394 AC: 60 AN: 152260 Hom.: 0 Cov.: 32 AF XY: 0.000430 AC XY: 32 AN XY: 74454

Gnomad4 AFR AF: 0.000168

Gnomad4 AMR AF: 0.000261

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.000754

Gnomad4 NFE AF: 0.000544

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.000549 Hom.: 0

Bravo AF: 0.000336

EpiCase AF: 0.00174

EpiControl AF: 0.00107

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 01, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 07, 2018	This variant is associated with the following publications: (PMID: 30564623, 26004199) -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 06, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2022	COL6A3: BP4 -

Bethlem myopathy 1A Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 18, 2024

This sequence change falls in intron 12 of the COL6A3 gene. It does not directly change the encoded amino acid sequence of the COL6A3 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs112825341, gnomAD 0.06%). This variant has been observed in individual(s) with clinical features of limb-girdle muscular dystrophy (PMID: 30564623). ClinVar contains an entry for this variant (Variation ID: 282789). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Muscular dystrophy Benign:1

Benign, criteria provided, single submitter

research

James R Lupski Laboratory, Baylor College Of Medicine

Jul 01, 2019

- -

Collagen 6-related myopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

COL6A3-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 26, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	7.3
DANN	Benign	0.64

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0018
dbscSNV1_RF	Benign	0.15
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

Publications

LitVar

Other links and lift over

dbSNP: rs112825341; hg19: chr2-238273074;