rs35273032

chr2-237367128-G-Achr2-237367128-G-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004369.4(COL6A3):c.5059C>T(p.Pro1687Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00128 in 1,614,152 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P1687P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0063 (6 hom., cov: 33)
  • Exomes 𝑓: 0.00075 (8 hom.)
• Consequence: COL6A3 NM_004369.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 5.65

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 -18 ACMG points.

• PM1: In a strand (size 16) in uniprot entity CO6A3_HUMAN there are 5 pathogenic changes around while only 1 benign (83%) in NM_004369.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.010222554).
• BP6: Variant 2-237367128-G-A is Benign according to our data. Variant chr2-237367128-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 94942.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00634 (966/152294) while in subpopulation AFR AF= 0.0213 (885/41536). AF 95% confidence interval is 0.0201. There are 6 homozygotes in gnomad4. There are 451 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 6 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL6A3	NM_004369.4	c.5059C>T	p.Pro1687Ser	missense_variant	11/44	ENST00000295550.9
COL6A3	NM_057167.4	c.4441C>T	p.Pro1481Ser	missense_variant	10/43
COL6A3	NM_057166.5	c.3238C>T	p.Pro1080Ser	missense_variant	8/41

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL6A3	ENST00000295550.9	c.5059C>T	p.Pro1687Ser	missense_variant	11/44	1	NM_004369.4	P1
COL6A3	ENST00000472056.5	c.3238C>T	p.Pro1080Ser	missense_variant	8/41	1
COL6A3	ENST00000353578.9	c.4441C>T	p.Pro1481Ser	missense_variant	10/43	5
COL6A3	ENST00000684597.1	c.391C>T	p.Pro131Ser	missense_variant	3/3

Frequencies

GnomAD3 genomes AF: 0.00632 AC: 962 AN: 152176 Hom.: 6 Cov.: 33

Gnomad AFR AF: 0.0213

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00268

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000220

Gnomad OTH AF: 0.00717

GnomAD3 exomes AF: 0.00187 AC: 469 AN: 251346 Hom.: 2 AF XY: 0.00141 AC XY: 192 AN XY: 135846

Gnomad AFR exome AF: 0.0223

Gnomad AMR exome AF: 0.00136

Gnomad ASJ exome AF: 0.00258

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000185

Gnomad OTH exome AF: 0.00179

GnomAD4 exome AF: 0.000748 AC: 1093 AN: 1461858 Hom.: 8 Cov.: 32 AF XY: 0.000663 AC XY: 482 AN XY: 727220

Gnomad4 AFR exome AF: 0.0215

Gnomad4 AMR exome AF: 0.00150

Gnomad4 ASJ exome AF: 0.00306

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000128

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000836

Gnomad4 OTH exome AF: 0.00184

GnomAD4 genome AF: 0.00634 AC: 966 AN: 152294 Hom.: 6 Cov.: 33 AF XY: 0.00606 AC XY: 451 AN XY: 74476

Gnomad4 AFR AF: 0.0213

Gnomad4 AMR AF: 0.00268

Gnomad4 ASJ AF: 0.00288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000220

Gnomad4 OTH AF: 0.00710

Alfa AF: 0.00120 Hom.: 5

Bravo AF: 0.00704

ESP6500AA AF: 0.0243 AC: 107

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00219 AC: 266

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000296

ClinVar

Significance: Benign/Likely 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)	Jan 02, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Ullrich congenital muscular dystrophy 1A;C4225336:Dystonia 27;CN029274:Bethlem myopathy 1A Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Aug 06, 2021

- -

Bethlem myopathy 1A Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 25, 2024

- -

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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 09, 2018

This variant is associated with the following publications: (PMID: 15689448) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.81
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.14
Cadd	Benign	23
Dann	Uncertain	1.0
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.95	D;D;D;D;.
MetaRNN	Benign	0.010	T;T;T;T;T
MetaSVM	Uncertain	-0.0076	T
MutationTaster	Benign	0.81	D;D;D;D;D;D
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-4.0	D;D;D;.;D
REVEL	Uncertain	0.58
Sift	Benign	0.11	T;T;T;.;T
Sift4G	Benign	0.22	T;T;T;T;T
Polyphen		1.0	D;P;.;.;D
Vest4		0.59
MVP		0.90
MPC		0.65
ClinPred		0.024	T
GERP RS		5.5
Varity_R		0.42
gMVP		0.59

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: rs35273032; hg19: chr2-238275771;