NM_001848.3:c.-19G>A

Variant names:

• chr21-45981832-G-A
• rs370096177
• NM_001848.3:c.-19G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001848.3(COL6A1):​c.-19G>A variant causes a 5 prime UTR premature start codon gain 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 Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 20)
  • Exomes 𝑓: 0.0000014 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: COL6A1 NM_001848.3 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.00
• Publications: 0 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).

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.-19G>A		5_prime_UTR_premature_start_codon_gain	Exon 1 of 35	NP_001839.2	P12109
	COL6A1	NM_001848.3	MANE Select	c.-19G>A		5_prime_UTR	Exon 1 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.-19G>A		5_prime_UTR_premature_start_codon_gain	Exon 1 of 35	ENSP00000355180.3	P12109
	COL6A1	ENST00000361866.8	TSL:1 MANE Select	c.-19G>A		5_prime_UTR	Exon 1 of 35	ENSP00000355180.3	P12109
	COL6A1	ENST00000866134.1		c.-19G>A		5_prime_UTR_premature_start_codon_gain	Exon 1 of 7	ENSP00000536193.1

Frequencies

GnomAD3 genomes AF: 0.0000133 AC: 2 AN: 150000 Hom.: 0 Cov.: 20

Gnomad AFR AF: 0.0000491

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000116 AC: 2 AN: 172756 AF XY: 0.0000106

Gnomad AFR exome AF: 0.000217

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000142 AC: 2 AN: 1411704 Hom.: 0 Cov.: 27 AF XY: 0.00000143 AC XY: 1 AN XY: 699118

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000312 AC: 1 AN: 32098

American (AMR) AF: 0.00 AC: 0 AN: 38850

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25292

East Asian (EAS) AF: 0.00 AC: 0 AN: 36648

South Asian (SAS) AF: 0.00 AC: 0 AN: 80456

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48544

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4260

European-Non Finnish (NFE) AF: 9.20e-7 AC: 1 AN: 1087232

Other (OTH) AF: 0.00 AC: 0 AN: 58324

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000133 AC: 2 AN: 150114 Hom.: 0 Cov.: 20 AF XY: 0.0000273 AC XY: 2 AN XY: 73282

African (AFR) AF: 0.0000489 AC: 2 AN: 40870

American (AMR) AF: 0.00 AC: 0 AN: 15052

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3458

East Asian (EAS) AF: 0.00 AC: 0 AN: 4980

South Asian (SAS) AF: 0.00 AC: 0 AN: 4648

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10402

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67416

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	15
DANN	Benign	0.79
PhyloP100		2.0
PromoterAI		-0.076	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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: rs370096177; hg19: chr21-47401746;