rs535807983

Variant names:

• chr21-45981786-C-G
• rs535807983
• NM_001848.3:c.-65C>G

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS1

The NM_001848.3(COL6A1):​c.-65C>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00037 (0 hom., cov: 20)
  • Exomes 𝑓: 0.00088 (1 hom.)
• Consequence: COL6A1 NM_001848.3 5_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0150

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]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 21-45981786-C-G is Benign according to our data. Variant chr21-45981786-C-G is described in ClinVar as [Benign]. Clinvar id is 340306.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000366 (54/147626) while in subpopulation NFE AF= 0.000687 (46/66912). AF 95% confidence interval is 0.000529. There are 0 homozygotes in gnomad4. There are 21 alleles in male gnomad4 subpopulation. Median coverage is 20. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL6A1	NM_001848.3	c.-65C>G		5_prime_UTR_variant	Exon 1 of 35	ENST00000361866.8	NP_001839.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL6A1	ENST00000361866	c.-65C>G		5_prime_UTR_variant	Exon 1 of 35	1	NM_001848.3	ENSP00000355180.3

Frequencies

GnomAD3 genomes AF: 0.000366 AC: 54 AN: 147518 Hom.: 0 Cov.: 20

Gnomad AFR AF: 0.0000754

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000204

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000994

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000687

Gnomad OTH AF: 0.000494

GnomAD4 exome AF: 0.000877 AC: 1009 AN: 1151016 Hom.: 1 Cov.: 15 AF XY: 0.000830 AC XY: 478 AN XY: 576014

Gnomad4 AFR exome AF: 0.000313

Gnomad4 AMR exome AF: 0.000531

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000940

Gnomad4 NFE exome AF: 0.00106

Gnomad4 OTH exome AF: 0.00108

GnomAD4 genome AF: 0.000366 AC: 54 AN: 147626 Hom.: 0 Cov.: 20 AF XY: 0.000292 AC XY: 21 AN XY: 71912

Gnomad4 AFR AF: 0.0000752

Gnomad4 AMR AF: 0.000203

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000994

Gnomad4 NFE AF: 0.000687

Gnomad4 OTH AF: 0.000489

Alfa AF: 0.000555 Hom.: 0

Bravo AF: 0.000465

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Collagen 6-related myopathy Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	8.5
DANN	Benign	0.70

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

Publications

LitVar

Other links and lift over

dbSNP: rs535807983; hg19: chr21-47401700;