rs201525908

Variant names:

• chr21-45990417-G-A
• rs201525908
• NM_001848.3:c.997G>A
• COL6A1 p.Val333Met

Your query was ambiguous. Multiple possible variants found:

• chr21-45990417-G-A
• chr21-45990417-G-T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001848.3(COL6A1):​c.997G>A​(p.Val333Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000375 in 1,225,138 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V333L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 0)
  • Exomes 𝑓: 0.00036 (4 hom.)
• Consequence: COL6A1 NM_001848.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 1.82
• Publications: 2 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: 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 -18 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 6 benign, 6 uncertain in NM_001848.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.009840518).
• BP6: Variant 21-45990417-G-A is Benign according to our data. Variant chr21-45990417-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 282116.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00106 (33/30992) while in subpopulation SAS AF = 0.0168 (15/894). AF 95% confidence interval is 0.0103. There are 0 homozygotes in GnomAd4. There are 18 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 4 SD,AR,AD gene

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.997G>A	p.Val333Met	missense	Exon 13 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.997G>A	p.Val333Met	missense	Exon 13 of 35	ENSP00000355180.3	P12109
	COL6A1	ENST00000866134.1		c.564+3756G>A		intron	N/A	ENSP00000536193.1

Frequencies

GnomAD3 genomes AF: 0.00103 AC: 32 AN: 30944 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000315

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000389

Gnomad ASJ AF: 0.00139

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0156

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0119

Gnomad NFE AF: 0.000802

Gnomad OTH AF: 0.00273

GnomAD2 exomes AF: 0.000904 AC: 224 AN: 247696 AF XY: 0.00115

Gnomad AFR exome AF: 0.0000629

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.00100

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000242

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.000358 AC: 427 AN: 1194146 Hom.: 4 Cov.: 50 AF XY: 0.000466 AC XY: 275 AN XY: 590398

African (AFR) AF: 0.0000754 AC: 2 AN: 26522

American (AMR) AF: 0.0000839 AC: 3 AN: 35772

Ashkenazi Jewish (ASJ) AF: 0.000732 AC: 13 AN: 17752

East Asian (EAS) AF: 0.00 AC: 0 AN: 19366

South Asian (SAS) AF: 0.00417 AC: 292 AN: 70058

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32658

Middle Eastern (MID) AF: 0.00223 AC: 10 AN: 4492

European-Non Finnish (NFE) AF: 0.0000890 AC: 84 AN: 943346

Other (OTH) AF: 0.000521 AC: 23 AN: 44180

GnomAD4 genome AF: 0.00106 AC: 33 AN: 30992 Hom.: 0 Cov.: 0 AF XY: 0.00122 AC XY: 18 AN XY: 14782

African (AFR) AF: 0.000314 AC: 3 AN: 9550

American (AMR) AF: 0.000388 AC: 1 AN: 2580

Ashkenazi Jewish (ASJ) AF: 0.00139 AC: 1 AN: 718

East Asian (EAS) AF: 0.00 AC: 0 AN: 936

South Asian (SAS) AF: 0.0168 AC: 15 AN: 894

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 1948

Middle Eastern (MID) AF: 0.0132 AC: 1 AN: 76

European-Non Finnish (NFE) AF: 0.000802 AC: 11 AN: 13716

Other (OTH) AF: 0.00263 AC: 1 AN: 380

Alfa AF: 0.000380 Hom.: 0

Bravo AF: 0.000264

EpiCase AF: 0.000273

EpiControl AF: 0.000415

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)
-	-	1	Bethlem myopathy 1A (1)
-	-	1	COL6A1-related disorder (1)
-	-	1	Collagen 6-related myopathy (1)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.055
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	15
DANN	Benign	0.93
DEOGEN2	Benign	0.32	T
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.39
FATHMM_MKL	Benign	0.34	N
LIST_S2	Benign	0.76	T
M_CAP	Benign	0.048	D
MetaRNN	Benign	0.0098	T
MetaSVM	Uncertain	-0.23	T
MutationAssessor	Benign	1.3	L
PhyloP100		1.8
PrimateAI	Benign	0.37	T
PROVEAN	Benign	1.8	N
REVEL	Benign	0.12
Sift	Benign	0.32	T
Sift4G	Benign	0.37	T
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.045
gMVP		0.41
Mutation Taster		=99/1	polymorphism

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: rs201525908;

hg19: chr21-47410331;

COSMIC: COSV62612092;

COSMIC: COSV62612092;