21-45984483-A-G

Position:

• chr21-45984483-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001848.3(COL6A1):​c.428+14A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.856 in 1,605,828 control chromosomes in the GnomAD database, including 589,019 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.87 (57704 hom., cov: 35)
  • Exomes 𝑓: 0.85 (531315 hom.)
• Consequence: COL6A1 NM_001848.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -3.77

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 (BayesDel_noAF=-0.83).
• BP6: Variant 21-45984483-A-G is Benign according to our data. Variant chr21-45984483-A-G is described in ClinVar as [Benign]. Clinvar id is 93873.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-45984483-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.904 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL6A1	NM_001848.3	c.428+14A>G		intron_variant		ENST00000361866.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL6A1	ENST00000361866.8	c.428+14A>G		intron_variant		1	NM_001848.3	P1

Frequencies

GnomAD3 genomes AF: 0.870 AC: 132463 AN: 152190 Hom.: 57653 Cov.: 35

Gnomad AFR AF: 0.893

Gnomad AMI AF: 0.877

Gnomad AMR AF: 0.862

Gnomad ASJ AF: 0.839

Gnomad EAS AF: 0.925

Gnomad SAS AF: 0.860

Gnomad FIN AF: 0.887

Gnomad MID AF: 0.889

Gnomad NFE AF: 0.854

Gnomad OTH AF: 0.881

GnomAD3 exomes AF: 0.860 AC: 207620 AN: 241302 Hom.: 89526 AF XY: 0.859 AC XY: 113376 AN XY: 131914

Gnomad AFR exome AF: 0.895

Gnomad AMR exome AF: 0.829

Gnomad ASJ exome AF: 0.827

Gnomad EAS exome AF: 0.923

Gnomad SAS exome AF: 0.854

Gnomad FIN exome AF: 0.883

Gnomad NFE exome AF: 0.856

Gnomad OTH exome AF: 0.860

GnomAD4 exome AF: 0.855 AC: 1242131 AN: 1453520 Hom.: 531315 Cov.: 41 AF XY: 0.855 AC XY: 618179 AN XY: 723386

Gnomad4 AFR exome AF: 0.891

Gnomad4 AMR exome AF: 0.835

Gnomad4 ASJ exome AF: 0.832

Gnomad4 EAS exome AF: 0.941

Gnomad4 SAS exome AF: 0.855

Gnomad4 FIN exome AF: 0.884

Gnomad4 NFE exome AF: 0.850

Gnomad4 OTH exome AF: 0.857

GnomAD4 genome AF: 0.870 AC: 132573 AN: 152308 Hom.: 57704 Cov.: 35 AF XY: 0.870 AC XY: 64771 AN XY: 74470

Gnomad4 AFR AF: 0.893

Gnomad4 AMR AF: 0.862

Gnomad4 ASJ AF: 0.839

Gnomad4 EAS AF: 0.926

Gnomad4 SAS AF: 0.860

Gnomad4 FIN AF: 0.887

Gnomad4 NFE AF: 0.854

Gnomad4 OTH AF: 0.882

Alfa AF: 0.859 Hom.: 10329

Bravo AF: 0.870

Asia WGS AF: 0.903 AC: 3140 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 14, 2014	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 22, 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	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Bethlem myopathy 1A Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 30, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

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. -

Ullrich congenital muscular dystrophy 1A Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.11
DANN	Benign	0.46

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: rs3746993; hg19: chr21-47404397;