rs11553519

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

18

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]

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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
COL6A1NM_001848.3 linkc.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
COL6A1ENST00000361866.8 linkc.347G>A p.Ser116Asn missense_variant 3/351 NM_001848.3 ENSP00000355180.3 P12109

Frequencies

GnomAD3 genomes
AF:
0.0455
AC:
6926
AN:
152264
Hom.:
165
Cov.:
35
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.:
33
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.:
35
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:
93
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 providedclinical testingGenetic 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 providedclinical testingClinical Genetics, Academic Medical Center-- -
Benign, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineMar 28, 2016Variant 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 submitterclinical testingAthena DiagnosticsDec 12, 2023- -
Benign, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Aug 28, 2012- -
Benign, criteria provided, single submitterclinical testingGeneDxJan 11, 2016This 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 providedclinical testingDiagnostic Laboratory, Department of Genetics, University Medical Center Groningen-- -
Benign, no assertion criteria providedclinical testingLaboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)-- -
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact Sciences-- -
Benign, no assertion criteria providedclinical testingGenome Diagnostics Laboratory, University Medical Center Utrecht-- -
Benign, no assertion criteria providedclinical testingJoint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+-- -
Collagen 6-related myopathy Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaMar 06, 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), LabcorpFeb 01, 2024- -
not provided Benign:1
Benign, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.093
BayesDel_addAF
Benign
-0.56
T
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
N
LIST_S2
Benign
0.52
T;T
MetaRNN
Benign
0.0022
T;T
MetaSVM
Benign
-0.98
T
MutationAssessor
Benign
0.40
N;.
PrimateAI
Benign
0.44
T
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
T
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.

Other links and lift over

dbSNP: rs11553519; hg19: chr21-47404302; COSMIC: COSV62613704; COSMIC: COSV62613704; API