rs34978064

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_StrongBP6_Very_StrongBP7BS2

The NM_004369.4(COL6A3):​c.1761C>T​(p.Ala587Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00171 in 1,614,188 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0014 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0017 ( 6 hom. )

Consequence

COL6A3
NM_004369.4 synonymous

Scores

2

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -3.61
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -17 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.82).
BP6
Variant 2-237381051-G-A is Benign according to our data. Variant chr2-237381051-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 197762.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP7
Synonymous conserved (PhyloP=-3.61 with no splicing effect.
BS2
High Homozygotes in GnomAdExome4 at 6 SD gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
COL6A3NM_004369.4 linkuse as main transcriptc.1761C>T p.Ala587Ala synonymous_variant 5/44 ENST00000295550.9 NP_004360.2 P12111-1D9ZGF2Q8N4Z1Q63HQ4

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
COL6A3ENST00000295550.9 linkuse as main transcriptc.1761C>T p.Ala587Ala synonymous_variant 5/441 NM_004369.4 ENSP00000295550.4 P12111-1

Frequencies

GnomAD3 genomes
AF:
0.00142
AC:
216
AN:
152194
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000482
Gnomad AMI
AF:
0.0175
Gnomad AMR
AF:
0.000720
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.0000941
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00240
Gnomad OTH
AF:
0.00239
GnomAD3 exomes
AF:
0.00129
AC:
325
AN:
251458
Hom.:
1
AF XY:
0.00130
AC XY:
177
AN XY:
135912
show subpopulations
Gnomad AFR exome
AF:
0.000308
Gnomad AMR exome
AF:
0.000405
Gnomad ASJ exome
AF:
0.0000992
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000163
Gnomad FIN exome
AF:
0.000231
Gnomad NFE exome
AF:
0.00254
Gnomad OTH exome
AF:
0.000977
GnomAD4 exome
AF:
0.00174
AC:
2547
AN:
1461876
Hom.:
6
Cov.:
32
AF XY:
0.00164
AC XY:
1196
AN XY:
727242
show subpopulations
Gnomad4 AFR exome
AF:
0.000358
Gnomad4 AMR exome
AF:
0.000470
Gnomad4 ASJ exome
AF:
0.0000765
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000336
Gnomad4 FIN exome
AF:
0.000374
Gnomad4 NFE exome
AF:
0.00213
Gnomad4 OTH exome
AF:
0.00161
GnomAD4 genome
AF:
0.00142
AC:
216
AN:
152312
Hom.:
0
Cov.:
33
AF XY:
0.00130
AC XY:
97
AN XY:
74464
show subpopulations
Gnomad4 AFR
AF:
0.000481
Gnomad4 AMR
AF:
0.000719
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.0000941
Gnomad4 NFE
AF:
0.00240
Gnomad4 OTH
AF:
0.00237
Alfa
AF:
0.00191
Hom.:
0
Bravo
AF:
0.00152
Asia WGS
AF:
0.000289
AC:
1
AN:
3478
EpiCase
AF:
0.00174
EpiControl
AF:
0.00261

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:3
Likely benign, criteria provided, single submitterclinical testingGeneDxJul 14, 2020This variant is associated with the following publications: (PMID: 30564623) -
Likely benign, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -
Likely benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenMay 01, 2024COL6A3: BP4, BP7 -
not specified Benign:2
Likely benign, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Jul 11, 2016- -
Likely benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact Sciences-- -
Collagen 6-related myopathy Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 12, 2018This 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. -
Bethlem myopathy 1A Benign:1
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 28, 2024- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.82
CADD
Benign
1.8
DANN
Benign
0.40

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs34978064; hg19: chr2-238289694; COSMIC: COSV99799211; API