rs117345850

Positions:

• chr2-237368554-G-A
• chr2-237368554-G-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_004369.4(COL6A3):​c.4900+9C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000524 in 1,613,802 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00038 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00054 (6 hom.)
• Consequence: COL6A3 NM_004369.4 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:5
• Conservation: PhyloP100: -0.393

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 2-237368554-G-A is Benign according to our data. Variant chr2-237368554-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 285987.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Benign=2, Uncertain_significance=2}.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000381 (58/152198) while in subpopulation EAS AF= 0.00599 (31/5174). AF 95% confidence interval is 0.00434. There are 2 homozygotes in gnomad4. There are 32 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 2 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL6A3	NM_004369.4	c.4900+9C>T		intron_variant		ENST00000295550.9	NP_004360.2
COL6A3	NM_057166.5	c.3079+9C>T		intron_variant			NP_476507.3
COL6A3	NM_057167.4	c.4282+9C>T		intron_variant			NP_476508.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL6A3	ENST00000295550.9	c.4900+9C>T		intron_variant		1	NM_004369.4	ENSP00000295550	P1
COL6A3	ENST00000472056.5	c.3079+9C>T		intron_variant		1		ENSP00000418285
COL6A3	ENST00000353578.9	c.4282+9C>T		intron_variant		5		ENSP00000315873
COL6A3	ENST00000684597.1	c.230+9C>T		intron_variant				ENSP00000508021

Frequencies

GnomAD3 genomes AF: 0.000381 AC: 58 AN: 152080 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.00598

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000654 AC: 164 AN: 250956 Hom.: 1 AF XY: 0.000634 AC XY: 86 AN XY: 135740

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000347

Gnomad ASJ exome AF: 0.00367

Gnomad EAS exome AF: 0.00370

Gnomad SAS exome AF: 0.000817

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000124

Gnomad OTH exome AF: 0.000652

GnomAD4 exome AF: 0.000538 AC: 787 AN: 1461604 Hom.: 6 Cov.: 33 AF XY: 0.000539 AC XY: 392 AN XY: 727032

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.000313

Gnomad4 ASJ exome AF: 0.00402

Gnomad4 EAS exome AF: 0.0124

Gnomad4 SAS exome AF: 0.000696

Gnomad4 FIN exome AF: 0.0000374

Gnomad4 NFE exome AF: 0.0000711

Gnomad4 OTH exome AF: 0.000530

GnomAD4 genome AF: 0.000381 AC: 58 AN: 152198 Hom.: 2 Cov.: 32 AF XY: 0.000430 AC XY: 32 AN XY: 74418

Gnomad4 AFR AF: 0.0000482

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00346

Gnomad4 EAS AF: 0.00599

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.0000943

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000327 Hom.: 0

Bravo AF: 0.000385

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2022	COL6A3: BS1 -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 02, 2016	- -

Dystonia 27 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Department of Neurology, Xijing Hospital, Fourth Military Medical University

Mar 01, 2022

- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Sep 21, 2016

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Bethlem myopathy 1A Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 09, 2024

- -

Collagen 6-related myopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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

Jun 03, 2019

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	-0.92
CADD	Benign	0.41
DANN	Benign	0.45

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

Publications

LitVar

Other links and lift over

dbSNP: rs117345850; hg19: chr2-238277197;