chr21-45985535-T-C

Variant names:

• chr21-45985535-T-C
• rs760437
• NM_001848.3:c.429-991T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001848.3(COL6A1):​c.429-991T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.873 in 152,186 control chromosomes in the GnomAD database, including 58,051 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.87 (58051 hom., cov: 32)
• Consequence: COL6A1 NM_001848.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.681
• Publications: 1 publications found

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 Gene-Disease associations (from GenCC):

• collagen 6-related myopathy

  Inheritance: AD, AR Classification: DEFINITIVE Submitted by: ClinGen
• Bethlem myopathy 1A

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, G2P
• Ullrich congenital muscular dystrophy 1A

  Inheritance: AD, AR Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• Bethlem myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Ullrich congenital muscular dystrophy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.99).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.905 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL6A1	NM_001848.3	c.429-991T>C		intron_variant	Intron 3 of 34	ENST00000361866.8	NP_001839.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL6A1	ENST00000361866.8	c.429-991T>C		intron_variant	Intron 3 of 34	1	NM_001848.3	ENSP00000355180.3

Frequencies

GnomAD3 genomes AF: 0.873 AC: 132812 AN: 152068 Hom.: 58000 Cov.: 32

Gnomad AFR AF: 0.894

Gnomad AMI AF: 0.882

Gnomad AMR AF: 0.864

Gnomad ASJ AF: 0.840

Gnomad EAS AF: 0.926

Gnomad SAS AF: 0.852

Gnomad FIN AF: 0.888

Gnomad MID AF: 0.883

Gnomad NFE AF: 0.860

Gnomad OTH AF: 0.881

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.873 AC: 132923 AN: 152186 Hom.: 58051 Cov.: 32 AF XY: 0.872 AC XY: 64896 AN XY: 74400

African (AFR) AF: 0.894 AC: 37102 AN: 41516

American (AMR) AF: 0.864 AC: 13225 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.840 AC: 2916 AN: 3470

East Asian (EAS) AF: 0.927 AC: 4778 AN: 5156

South Asian (SAS) AF: 0.852 AC: 4110 AN: 4826

European-Finnish (FIN) AF: 0.888 AC: 9417 AN: 10610

Middle Eastern (MID) AF: 0.891 AC: 262 AN: 294

European-Non Finnish (NFE) AF: 0.860 AC: 58443 AN: 67984

Other (OTH) AF: 0.883 AC: 1866 AN: 2114

Alfa AF: 0.853 Hom.: 2725

Bravo AF: 0.873

Asia WGS AF: 0.902 AC: 3136 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	0.41
DANN	Benign	0.54
PhyloP100		-0.68
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs760437; hg19: chr21-47405449;