rs140547835

Variant names:

• chr21-46002700-G-T
• rs140547835
• NM_001848.3:c.2424G>T

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.2424G>T​(p.Gln808His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00553 in 1,611,966 control chromosomes in the GnomAD database, including 336 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0088 (33 hom., cov: 35)
  • Exomes 𝑓: 0.0052 (303 hom.)
• Consequence: COL6A1 NM_001848.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.671
• Publications: 5 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: AR, AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, G2P
• collagen 6-related myopathy

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

  Inheritance: AD, AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• 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 (MetaRNN=0.00200212).
• BP6: Variant 21-46002700-G-T is Benign according to our data. Variant chr21-46002700-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 93853.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0745 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.2424G>T	p.Gln808His	missense	Exon 33 of 35	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.2424G>T	p.Gln808His	missense	Exon 33 of 35	ENSP00000355180.3	P12109
	COL6A1	ENST00000498614.5	TSL:1	n.658G>T		non_coding_transcript_exon	Exon 4 of 6
	COL6A1	ENST00000866134.1		c.738G>T	p.Gln246His	missense	Exon 5 of 7	ENSP00000536193.1

Frequencies

GnomAD3 genomes AF: 0.00878 AC: 1337 AN: 152242 Hom.: 33 Cov.: 35

Gnomad AFR AF: 0.000941

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0254

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0704

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00206

Gnomad OTH AF: 0.00813

GnomAD2 exomes AF: 0.0183 AC: 4529 AN: 247814 AF XY: 0.0148

Gnomad AFR exome AF: 0.00162

Gnomad AMR exome AF: 0.0848

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0600

Gnomad NFE exome AF: 0.00232

Gnomad OTH exome AF: 0.0114

GnomAD4 exome AF: 0.00519 AC: 7581 AN: 1459606 Hom.: 303 Cov.: 52 AF XY: 0.00470 AC XY: 3416 AN XY: 726128

African (AFR) AF: 0.000747 AC: 25 AN: 33464

American (AMR) AF: 0.0766 AC: 3393 AN: 44276

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26120

East Asian (EAS) AF: 0.000631 AC: 25 AN: 39648

South Asian (SAS) AF: 0.0000697 AC: 6 AN: 86136

European-Finnish (FIN) AF: 0.0630 AC: 3306 AN: 52472

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.000508 AC: 565 AN: 1111400

Other (OTH) AF: 0.00431 AC: 260 AN: 60324

GnomAD4 genome AF: 0.00878 AC: 1338 AN: 152360 Hom.: 33 Cov.: 35 AF XY: 0.0113 AC XY: 844 AN XY: 74504

African (AFR) AF: 0.000938 AC: 39 AN: 41580

American (AMR) AF: 0.0255 AC: 390 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000579 AC: 3 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.0704 AC: 749 AN: 10632

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00206 AC: 140 AN: 68030

Other (OTH) AF: 0.00804 AC: 17 AN: 2114

Alfa AF: 0.00327 Hom.: 31

Bravo AF: 0.00747

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.00163 AC: 14

ExAC AF: 0.0160 AC: 1944

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	not provided (2)
-	-	1	Bethlem myopathy 1A (1)
-	-	1	Collagen 6-related myopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.19	T
Eigen	Benign	-0.92
Eigen_PC	Benign	-0.84
FATHMM_MKL	Benign	0.030	N
LIST_S2	Benign	0.63	T
MetaRNN	Benign	0.0020	T
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	1.2	L
PhyloP100		-0.67
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.14
Sift	Benign	0.29	T
Sift4G	Benign	0.35	T
Polyphen		0.0	B
Vest4		0.097
MutPred		0.49		Loss of sheet (P = 0.0457)
MPC		0.21
ClinPred		0.0078	T
GERP RS		0.52
Varity_R		0.083
gMVP		0.41
Mutation Taster		=97/3	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs140547835; hg19: chr21-47422614; COSMIC: COSV62612407; COSMIC: COSV62612407;