21-45984483-A-G

Variant names:

• chr21-45984483-A-G
• rs3746993
• NM_001848.3:c.428+14A>G

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.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:11
• Conservation: PhyloP100: -3.77
• Publications: 12 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):

• Bethlem myopathy 1A

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, G2P
• collagen 6-related myopathy

  Inheritance: AD, AR, SD Classification: DEFINITIVE Submitted by: ClinGen
• Ullrich congenital muscular dystrophy 1A

  Inheritance: AR, AD 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=-0.83).
• BP6: Variant 21-45984483-A-G is Benign according to our data. Variant chr21-45984483-A-G is described in ClinVar as Benign. ClinVar VariationId is 93873.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.904 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL6A1	NM_001848.3	MANE Select	c.428+14A>G		intron	N/A	NP_001839.2	P12109

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL6A1	ENST00000361866.8	TSL:1 MANE Select	c.428+14A>G		intron	N/A	ENSP00000355180.3	P12109
	COL6A1	ENST00000866134.1		c.428+14A>G		intron	N/A	ENSP00000536193.1

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

GnomAD2 exomes AF: 0.860 AC: 207620 AN: 241302 AF XY: 0.859

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 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

African (AFR) AF: 0.891 AC: 29815 AN: 33458

American (AMR) AF: 0.835 AC: 37302 AN: 44684

Ashkenazi Jewish (ASJ) AF: 0.832 AC: 21741 AN: 26116

East Asian (EAS) AF: 0.941 AC: 37356 AN: 39686

South Asian (SAS) AF: 0.855 AC: 73727 AN: 86206

European-Finnish (FIN) AF: 0.884 AC: 40708 AN: 46058

Middle Eastern (MID) AF: 0.861 AC: 4962 AN: 5764

European-Non Finnish (NFE) AF: 0.850 AC: 944839 AN: 1111278

Other (OTH) AF: 0.857 AC: 51681 AN: 60270

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

African (AFR) AF: 0.893 AC: 37102 AN: 41566

American (AMR) AF: 0.862 AC: 13200 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.839 AC: 2911 AN: 3470

East Asian (EAS) AF: 0.926 AC: 4779 AN: 5162

South Asian (SAS) AF: 0.860 AC: 4153 AN: 4830

European-Finnish (FIN) AF: 0.887 AC: 9418 AN: 10618

Middle Eastern (MID) AF: 0.898 AC: 264 AN: 294

European-Non Finnish (NFE) AF: 0.854 AC: 58081 AN: 68032

Other (OTH) AF: 0.882 AC: 1867 AN: 2116

Alfa AF: 0.859 Hom.: 10329

Bravo AF: 0.870

Asia WGS AF: 0.903 AC: 3140 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	2	Bethlem myopathy 1A (2)
-	-	1	Collagen 6-related myopathy (1)
-	-	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	-0.83
CADD	Benign	0.11
DANN	Benign	0.46
PhyloP100		-3.8
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs3746993;

hg19: chr21-47404397;