rs1556425727

Positions:

• chr21-45990407-GGTGGACGGCGTGAAGGTGACTGGGGGGAGATAGGATGGACGGGGAGGGACGAGGAGGAATGGGGCGAGATGGGGAGGGACGGA-G

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 3P and 8B. PVS1_Moderate PP3 BP6_Very_Strong

The NM_001848.3(COL6A1):​c.1002+6_1002+88del variant causes a splice donor, splice donor 5th base, coding sequence, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000132 in 1,294,916 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0036 (0 hom., cov: 0)
  • Exomes 𝑓: 0.00013 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: COL6A1 NM_001848.3 splice_donor, splice_donor_5th_base, coding_sequence, intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2 O:1
• Conservation: PhyloP100: 8.34

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 Likely_benign. Variant got -5 ACMG points.

• PVS1: Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.01425332 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• BP6: Variant 21-45990407-GGTGGACGGCGTGAAGGTGACTGGGGGGAGATAGGATGGACGGGGAGGGACGAGGAGGAATGGGGCGAGATGGGGAGGGACGGA-G is Benign according to our data. Variant chr21-45990407-GGTGGACGGCGTGAAGGTGACTGGGGGGAGATAGGATGGACGGGGAGGGACGAGGAGGAATGGGGCGAGATGGGGAGGGACGGA-G is described in ClinVar as [Likely_benign]. Clinvar id is 543025.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-45990407-GGTGGACGGCGTGAAGGTGACTGGGGGGAGATAGGATGGACGGGGAGGGACGAGGAGGAATGGGGCGAGATGGGGAGGGACGGA-G is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL6A1	NM_001848.3	c.1002+6_1002+88del		splice_donor_variant, splice_donor_5th_base_variant, coding_sequence_variant, intron_variant	13/35	ENST00000361866.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL6A1	ENST00000361866.8	c.1002+6_1002+88del		splice_donor_variant, splice_donor_5th_base_variant, coding_sequence_variant, intron_variant	13/35	1	NM_001848.3	P1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 173 AN: 48458 Hom.: 0 Cov.: 0 FAILED QC

Gnomad AFR AF: 0.00400

Gnomad AMI AF: 0.00617

Gnomad AMR AF: 0.00429

Gnomad ASJ AF: 0.00334

Gnomad EAS AF: 0.00202

Gnomad SAS AF: 0.00476

Gnomad FIN AF: 0.00626

Gnomad MID AF: 0.0217

Gnomad NFE AF: 0.00269

Gnomad OTH AF: 0.00318

GnomAD4 exome AF: 0.000132 AC: 171 AN: 1294916 Hom.: 0 AF XY: 0.000121 AC XY: 78 AN XY: 643186

Gnomad4 AFR exome AF: 0.0000347

Gnomad4 AMR exome AF: 0.000101

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000251

Gnomad4 FIN exome AF: 0.0000755

Gnomad4 NFE exome AF: 0.000152

Gnomad4 OTH exome AF: 0.000100

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00357 AC: 173 AN: 48508 Hom.: 0 Cov.: 0 AF XY: 0.00382 AC XY: 89 AN XY: 23292

Gnomad4 AFR AF: 0.00398

Gnomad4 AMR AF: 0.00429

Gnomad4 ASJ AF: 0.00334

Gnomad4 EAS AF: 0.00203

Gnomad4 SAS AF: 0.00476

Gnomad4 FIN AF: 0.00626

Gnomad4 NFE AF: 0.00269

Gnomad4 OTH AF: 0.00311

Alfa AF: 0.000594 Hom.: 0

ClinVar

Significance: Likely benign

Submissions summary: Benign:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

COL6A1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 27, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Bethlem myopathy 1A Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 06, 2023

- -

Ullrich congenital muscular dystrophy 1A;CN029274:Bethlem myopathy 1A Other:1

not provided, no classification provided

phenotyping only

GenomeConnect - Invitae Patient Insights Network

-

Variant interpreted as Likely benign and reported on 03-09-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1556425727; hg19: chr21-47410321;