rs73998889

Variant names:

• chr2-237360038-G-A
• rs73998889
• NM_004369.4:c.6282+50C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004369.4(COL6A3):​c.6282+50C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0072 in 1,585,368 control chromosomes in the GnomAD database, including 363 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.028 (174 hom., cov: 32)
  • Exomes 𝑓: 0.0050 (189 hom.)
• Consequence: COL6A3 NM_004369.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.84
• Publications: 3 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, AR, SD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Ambry Genetics
• collagen 6-related myopathy

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

  Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
• dystonia 27

  Inheritance: AR Classification: STRONG, SUPPORTIVE, LIMITED, NO_KNOWN Submitted by: Illumina, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics, Orphanet
• Ullrich congenital muscular dystrophy 1A

  Inheritance: AR, AD, SD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 2-237360038-G-A is Benign according to our data. Variant chr2-237360038-G-A is described in ClinVar as Benign. ClinVar VariationId is 94960.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0849 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL6A3	NM_004369.4	c.6282+50C>T		intron_variant	Intron 17 of 43	ENST00000295550.9	NP_004360.2
COL6A3	NM_057167.4	c.5664+50C>T		intron_variant	Intron 16 of 42		NP_476508.2
COL6A3	NM_057166.5	c.4461+50C>T		intron_variant	Intron 14 of 40		NP_476507.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL6A3	ENST00000295550.9	c.6282+50C>T		intron_variant	Intron 17 of 43	1	NM_004369.4	ENSP00000295550.4
COL6A3	ENST00000472056.5	c.4461+50C>T		intron_variant	Intron 14 of 40	1		ENSP00000418285.1
COL6A3	ENST00000353578.9	c.5664+50C>T		intron_variant	Intron 16 of 42	5		ENSP00000315873.4

Frequencies

GnomAD3 genomes AF: 0.0278 AC: 4227 AN: 151968 Hom.: 173 Cov.: 32

Gnomad AFR AF: 0.0874

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0183

Gnomad ASJ AF: 0.00547

Gnomad EAS AF: 0.00369

Gnomad SAS AF: 0.00914

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.00268

Gnomad OTH AF: 0.0272

GnomAD2 exomes AF: 0.0103 AC: 2550 AN: 246956 AF XY: 0.00873

Gnomad AFR exome AF: 0.0887

Gnomad AMR exome AF: 0.0110

Gnomad ASJ exome AF: 0.00583

Gnomad EAS exome AF: 0.00313

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00274

Gnomad OTH exome AF: 0.00944

GnomAD4 exome AF: 0.00501 AC: 7183 AN: 1433282 Hom.: 189 Cov.: 28 AF XY: 0.00489 AC XY: 3491 AN XY: 714390

African (AFR) AF: 0.0882 AC: 2899 AN: 32866

American (AMR) AF: 0.0119 AC: 531 AN: 44508

Ashkenazi Jewish (ASJ) AF: 0.00632 AC: 164 AN: 25934

East Asian (EAS) AF: 0.00137 AC: 54 AN: 39514

South Asian (SAS) AF: 0.00923 AC: 787 AN: 85274

European-Finnish (FIN) AF: 0.0000937 AC: 5 AN: 53342

Middle Eastern (MID) AF: 0.0214 AC: 121 AN: 5650

European-Non Finnish (NFE) AF: 0.00178 AC: 1935 AN: 1086764

Other (OTH) AF: 0.0116 AC: 687 AN: 59430

GnomAD4 genome AF: 0.0278 AC: 4228 AN: 152086 Hom.: 174 Cov.: 32 AF XY: 0.0275 AC XY: 2043 AN XY: 74344

African (AFR) AF: 0.0873 AC: 3619 AN: 41466

American (AMR) AF: 0.0182 AC: 278 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00547 AC: 19 AN: 3472

East Asian (EAS) AF: 0.00350 AC: 18 AN: 5144

South Asian (SAS) AF: 0.00915 AC: 44 AN: 4810

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10590

Middle Eastern (MID) AF: 0.0374 AC: 11 AN: 294

European-Non Finnish (NFE) AF: 0.00268 AC: 182 AN: 67992

Other (OTH) AF: 0.0270 AC: 57 AN: 2114

Alfa AF: 0.0145 Hom.: 29

Bravo AF: 0.0322

Asia WGS AF: 0.0160 AC: 55 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 05, 2012

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 07, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.91
DANN	Benign	0.59
PhyloP100		-1.8
Mutation Taster		=100/0	polymorphism (auto)

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: rs73998889; hg19: chr2-238268681;