NM_001848.3:c.429-19G>A

Variant names:

• chr21-45986507-G-A
• rs741956
• NM_001848.3:c.429-19G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001848.3(COL6A1):​c.429-19G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.224 in 1,551,888 control chromosomes in the GnomAD database, including 42,114 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (3057 hom., cov: 32)
  • Exomes 𝑓: 0.23 (39057 hom.)
• Consequence: COL6A1 NM_001848.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -2.48
• Publications: 8 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 21-45986507-G-A is Benign according to our data. Variant chr21-45986507-G-A is described in ClinVar as Benign. ClinVar VariationId is 93876.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.239 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001848.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL6A1	NM_001848.3	MANE Select	c.429-19G>A		intron	N/A	NP_001839.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL6A1	ENST00000361866.8	TSL:1 MANE Select	c.429-19G>A		intron	N/A	ENSP00000355180.3
	COL6A1	ENST00000866134.1		c.429-19G>A		intron	N/A	ENSP00000536193.1

Frequencies

GnomAD3 genomes AF: 0.185 AC: 28093 AN: 151974 Hom.: 3055 Cov.: 32

Gnomad AFR AF: 0.102

Gnomad AMI AF: 0.206

Gnomad AMR AF: 0.186

Gnomad ASJ AF: 0.171

Gnomad EAS AF: 0.00830

Gnomad SAS AF: 0.0966

Gnomad FIN AF: 0.272

Gnomad MID AF: 0.0981

Gnomad NFE AF: 0.242

Gnomad OTH AF: 0.178

GnomAD2 exomes AF: 0.182 AC: 29123 AN: 159964 AF XY: 0.180

Gnomad AFR exome AF: 0.0976

Gnomad AMR exome AF: 0.156

Gnomad ASJ exome AF: 0.169

Gnomad EAS exome AF: 0.00567

Gnomad FIN exome AF: 0.270

Gnomad NFE exome AF: 0.243

Gnomad OTH exome AF: 0.189

GnomAD4 exome AF: 0.228 AC: 319313 AN: 1399796 Hom.: 39057 Cov.: 32 AF XY: 0.224 AC XY: 154871 AN XY: 690758

African (AFR) AF: 0.0981 AC: 3110 AN: 31700

American (AMR) AF: 0.159 AC: 5766 AN: 36156

Ashkenazi Jewish (ASJ) AF: 0.169 AC: 4253 AN: 25214

East Asian (EAS) AF: 0.00618 AC: 222 AN: 35914

South Asian (SAS) AF: 0.110 AC: 8745 AN: 79348

European-Finnish (FIN) AF: 0.265 AC: 12774 AN: 48138

Middle Eastern (MID) AF: 0.131 AC: 745 AN: 5686

European-Non Finnish (NFE) AF: 0.252 AC: 271825 AN: 1079552

Other (OTH) AF: 0.204 AC: 11873 AN: 58088

GnomAD4 genome AF: 0.185 AC: 28105 AN: 152092 Hom.: 3057 Cov.: 32 AF XY: 0.184 AC XY: 13691 AN XY: 74336

African (AFR) AF: 0.102 AC: 4230 AN: 41518

American (AMR) AF: 0.186 AC: 2844 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.171 AC: 592 AN: 3472

East Asian (EAS) AF: 0.00871 AC: 45 AN: 5168

South Asian (SAS) AF: 0.0975 AC: 469 AN: 4812

European-Finnish (FIN) AF: 0.272 AC: 2872 AN: 10578

Middle Eastern (MID) AF: 0.102 AC: 30 AN: 294

European-Non Finnish (NFE) AF: 0.242 AC: 16463 AN: 67954

Other (OTH) AF: 0.176 AC: 373 AN: 2114

Alfa AF: 0.133 Hom.: 373

Bravo AF: 0.176

Asia WGS AF: 0.0540 AC: 190 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	2	Bethlem myopathy 1A (2)
-	-	1	not provided (1)
-	-	1	Ullrich congenital muscular dystrophy 1A (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.054
DANN	Benign	0.59
PhyloP100		-2.5
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: rs741956; hg19: chr21-47406421; COSMIC: COSV62613620; COSMIC: COSV62613620;