rs201525908

Positions:

• chr21-45990417-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001848.3(COL6A1):​c.997G>A​(p.Val333Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000375 in 1,225,138 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V333L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 0)
  • Exomes 𝑓: 0.00036 (4 hom.)
• Consequence: COL6A1 NM_001848.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.82

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009840518).
• BP6: Variant 21-45990417-G-A is Benign according to our data. Variant chr21-45990417-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 282116.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00106 (33/30992) while in subpopulation SAS AF= 0.0168 (15/894). AF 95% confidence interval is 0.0103. There are 0 homozygotes in gnomad4. There are 18 alleles in male gnomad4 subpopulation. Median coverage is 0. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 4 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL6A1	NM_001848.3	c.997G>A	p.Val333Met	missense_variant	13/35	ENST00000361866.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL6A1	ENST00000361866.8	c.997G>A	p.Val333Met	missense_variant	13/35	1	NM_001848.3	P1

Frequencies

GnomAD3 genomes AF: 0.00103 AC: 32 AN: 30944 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000315

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000389

Gnomad ASJ AF: 0.00139

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0156

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0119

Gnomad NFE AF: 0.000802

Gnomad OTH AF: 0.00273

GnomAD3 exomes AF: 0.000904 AC: 224 AN: 247696 Hom.: 2 AF XY: 0.00115 AC XY: 155 AN XY: 134728

Gnomad AFR exome AF: 0.0000629

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.00100

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00587

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000242

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.000358 AC: 427 AN: 1194146 Hom.: 4 Cov.: 50 AF XY: 0.000466 AC XY: 275 AN XY: 590398

Gnomad4 AFR exome AF: 0.0000754

Gnomad4 AMR exome AF: 0.0000839

Gnomad4 ASJ exome AF: 0.000732

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00417

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000890

Gnomad4 OTH exome AF: 0.000521

GnomAD4 genome AF: 0.00106 AC: 33 AN: 30992 Hom.: 0 Cov.: 0 AF XY: 0.00122 AC XY: 18 AN XY: 14782

Gnomad4 AFR AF: 0.000314

Gnomad4 AMR AF: 0.000388

Gnomad4 ASJ AF: 0.00139

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0168

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000802

Gnomad4 OTH AF: 0.00263

Alfa AF: 0.000380 Hom.: 0

Bravo AF: 0.000264

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00109 AC: 132

EpiCase AF: 0.000273

EpiControl AF: 0.000415

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jul 21, 2015

- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 28, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

COL6A1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 23, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

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. -

Bethlem myopathy 1A Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 18, 2024

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 26, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.055
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	15
DANN	Benign	0.93
DEOGEN2	Benign	0.32	T;T
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.39
FATHMM_MKL	Benign	0.34	N
LIST_S2	Benign	0.76	T;T
M_CAP	Benign	0.048	D
MetaRNN	Benign	0.0098	T;T
MetaSVM	Uncertain	-0.23	T
MutationAssessor	Benign	1.3	L;.
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.37	T
PROVEAN	Benign	1.8	N;.
REVEL	Benign	0.12
Sift	Benign	0.32	T;.
Sift4G	Benign	0.37	T;T
Polyphen		0.16	B;.
Vest4		0.16
MVP		0.11
MPC		0.22
ClinPred		0.017	T
GERP RS		2.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.045
gMVP		0.41

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: rs201525908; hg19: chr21-47410331; COSMIC: COSV62612092; COSMIC: COSV62612092;