rs11553519

Positions:

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBA1

The NM_001848.3(COL6A1):c.347G>A(p.Ser116Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0444 in 1,612,750 control chromosomes in the GnomAD database, including 1,767 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.045 ( 165 hom., cov: 35)

Exomes 𝑓: 0.044 ( 1602 hom. )

Consequence

COL6A1
NM_001848.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:14

Conservation

PhyloP100: 0.897

Variant links:

Genes affected

COL6A1 (HGNC:2211): (collagen type VI alpha 1 chain) The collagens are a superfamily of proteins that play a role in maintaining the integrity of various tissues. Collagens are extracellular matrix proteins and have a triple-helical domain as their common structural element. Collagen VI is a major structural component of microfibrils. The basic structural unit of collagen VI is a heterotrimer of the alpha1(VI), alpha2(VI), and alpha3(VI) chains. The alpha2(VI) and alpha3(VI) chains are encoded by the COL6A2 and COL6A3 genes, respectively. The protein encoded by this gene is the alpha 1 subunit of type VI collagen (alpha1(VI) chain). Mutations in the genes that code for the collagen VI subunits result in the autosomal dominant disorder, Bethlem myopathy. [provided by RefSeq, Jul 2008]

COL6A1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -18 ACMG points.

PM1

In a region_of_interest N-terminal globular domain (size 236) in uniprot entity CO6A1_HUMAN there are 12 pathogenic changes around while only 1 benign (92%) in NM_001848.3

BP4

Computational evidence support a benign effect (MetaRNN=0.002249211).

BP6

Variant 21-45984388-G-A is Benign according to our data. Variant chr21-45984388-G-A is described in ClinVar as [Benign]. Clinvar id is 93872.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-45984388-G-A is described in Lovd as [Likely_pathogenic]. Variant chr21-45984388-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0527 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL6A1	NM_001848.3 link	c.347G>A	p.Ser116Asn	missense_variant	3/35	ENST00000361866.8	NP_001839.2	P12109A0A384P5H7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL6A1	ENST00000361866.8 link	c.347G>A	p.Ser116Asn	missense_variant	3/35	1	NM_001848.3	ENSP00000355180.3		P12109

Frequencies

GnomAD3 genomes

AF:

0.0455

AC:

6926

AN:

152264

Hom.:

165

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0362

Gnomad AMI

AF:

0.0186

Gnomad AMR

AF:

0.0319

Gnomad ASJ

AF:

0.0446

Gnomad EAS

AF:

0.00269

Gnomad SAS

AF:

0.0322

Gnomad FIN

AF:

0.0752

Gnomad MID

AF:

0.0506

Gnomad NFE

AF:

0.0541

Gnomad OTH

AF:

0.0468

GnomAD3 exomes

AF:

0.0424

AC:

10584

AN:

249534

Hom.:

276

AF XY:

0.0432

AC XY:

5853

AN XY:

135538

show subpopulations

Gnomad AFR exome

AF:

0.0338

Gnomad AMR exome

AF:

0.0243

Gnomad ASJ exome

AF:

0.0447

Gnomad EAS exome

AF:

0.00256

Gnomad SAS exome

AF:

0.0299

Gnomad FIN exome

AF:

0.0744

Gnomad NFE exome

AF:

0.0523

Gnomad OTH exome

AF:

0.0519

GnomAD4 exome

AF:

0.0443

AC:

64674

AN:

1460368

Hom.:

1602

Cov.:

AF XY:

0.0442

AC XY:

32081

AN XY:

726490

show subpopulations

Gnomad4 AFR exome

AF:

0.0332

Gnomad4 AMR exome

AF:

0.0254

Gnomad4 ASJ exome

AF:

0.0451

Gnomad4 EAS exome

AF:

0.00353

Gnomad4 SAS exome

AF:

0.0287

Gnomad4 FIN exome

AF:

0.0747

Gnomad4 NFE exome

AF:

0.0465

Gnomad4 OTH exome

AF:

0.0433

GnomAD4 genome

AF:

0.0455

AC:

6927

AN:

152382

Hom.:

165

Cov.:

AF XY:

0.0447

AC XY:

3330

AN XY:

74518

show subpopulations

Gnomad4 AFR

AF:

0.0361

Gnomad4 AMR

AF:

0.0317

Gnomad4 ASJ

AF:

0.0446

Gnomad4 EAS

AF:

0.00270

Gnomad4 SAS

AF:

0.0323

Gnomad4 FIN

AF:

0.0752

Gnomad4 NFE

AF:

0.0541

Gnomad4 OTH

AF:

0.0473

Alfa

AF:

0.0463

Hom.:

230

Bravo

AF:

0.0402

TwinsUK

AF:

0.0399

AC:

148

ALSPAC

AF:

0.0418

AC:

161

ESP6500AA

AF:

0.0284

AC:

125

ESP6500EA

AF:

0.0472

AC:

406

ExAC

AF:

0.0427

AC:

5168

Asia WGS

AF:

0.0270

AC:

AN:

3478

EpiCase

AF:

0.0511

EpiControl

AF:

0.0486

ClinVar

Significance: Benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:11

Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency in ESP (all): 531/13002=4% -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 12, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 28, 2012	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 11, 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. -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Collagen 6-related myopathy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 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. -

Bethlem myopathy 1A

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.093

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.53

CADD

Benign

7.6

DANN

Benign

0.95

DEOGEN2

Benign

0.22

T;T

Eigen

Benign

-0.93

Eigen_PC

Benign

-0.95

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.52

T;T

MetaRNN

Benign

0.0022

T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.40

N;.

PrimateAI

Benign

0.44

PROVEAN

Benign

-0.67

N;.

REVEL

Benign

0.19

Sift

Benign

0.51

T;.

Sift4G

Benign

0.35

T;T

Polyphen

0.14

B;.

Vest4

0.15

MPC

0.21

ClinPred

0.0054

GERP RS

1.4

Varity_R

0.049

gMVP

0.69

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over