chr1-1435798-T-TGGCGCGGAGC

Variant names:

• chr1-1435798-T-TGGCGCGGAGC
• rs749383814
• NM_022834.5:c.62_71dupGCGCGGAGCG

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1_Strong PP5_Very_Strong

The NM_022834.5(VWA1):​c.62_71dupGCGCGGAGCG​(p.Gly25ArgfsTer74) variant causes a frameshift, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000931 in 1,202,546 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.00067 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00097 (1 hom.)
• Consequence: VWA1 NM_022834.5 frameshift, splice_region
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10
• Conservation: PhyloP100: 0.706
• Publications: 1 publications found

Genes affected

VWA1 (HGNC:30910): (von Willebrand factor A domain containing 1) VWA1 belongs to the von Willebrand factor (VWF; MIM 613160) A (VWFA) domain superfamily of extracellular matrix proteins and appears to play a role in cartilage structure and function (Fitzgerald et al., 2002 [PubMed 12062410]).[supplied by OMIM, Nov 2010]

LOC107985729 (HGNC:):

LINC01770 (HGNC:52560): (long intergenic non-protein coding RNA 1770)

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 17 pathogenic variants in the truncated region.
• PP5: Variant 1-1435798-T-TGGCGCGGAGC is Pathogenic according to our data. Variant chr1-1435798-T-TGGCGCGGAGC is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 830327.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022834.5. 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
	VWA1	NM_022834.5	MANE Select	c.62_71dupGCGCGGAGCG	p.Gly25ArgfsTer74	frameshift splice_region	Exon 1 of 3	NP_073745.2
	VWA1	NM_199121.3		c.62_71dupGCGCGGAGCG	p.Gly25ArgfsTer53	frameshift splice_region	Exon 1 of 3	NP_954572.2	Q6PCB0-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VWA1	ENST00000476993.2	TSL:1 MANE Select	c.62_71dupGCGCGGAGCG	p.Gly25ArgfsTer74	frameshift splice_region	Exon 1 of 3	ENSP00000417185.1	Q6PCB0-1
	VWA1	ENST00000895635.1		c.62_71dupGCGCGGAGCG	p.Ala25ArgfsTer71	frameshift splice_region	Exon 1 of 3	ENSP00000565694.1
	VWA1	ENST00000895634.1		c.62_71dupGCGCGGAGCG	p.Asp25ArgfsTer79	frameshift splice_region	Exon 1 of 2	ENSP00000565693.1

Frequencies

GnomAD3 genomes AF: 0.000669 AC: 100 AN: 149504 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000510

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000665

Gnomad ASJ AF: 0.000292

Gnomad EAS AF: 0.000195

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000956

Gnomad OTH AF: 0.000971

GnomAD2 exomes AF: 0.00 AC: 0 AN: 16854 AF XY: 0.00

Gnomad AFR exome AF: 0.00

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 AF: 0.000969 AC: 1020 AN: 1052936 Hom.: 1 Cov.: 31 AF XY: 0.000991 AC XY: 507 AN XY: 511496

African (AFR) AF: 0.000749 AC: 15 AN: 20024

American (AMR) AF: 0.000455 AC: 4 AN: 8792

Ashkenazi Jewish (ASJ) AF: 0.0000841 AC: 1 AN: 11896

East Asian (EAS) AF: 0.0000715 AC: 1 AN: 13984

South Asian (SAS) AF: 0.0000772 AC: 3 AN: 38852

European-Finnish (FIN) AF: 0.0000549 AC: 1 AN: 18224

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2840

European-Non Finnish (NFE) AF: 0.00106 AC: 954 AN: 899360

Other (OTH) AF: 0.00105 AC: 41 AN: 38964

GnomAD4 genome AF: 0.000668 AC: 100 AN: 149610 Hom.: 0 Cov.: 32 AF XY: 0.000644 AC XY: 47 AN XY: 73002

African (AFR) AF: 0.000509 AC: 21 AN: 41254

American (AMR) AF: 0.000664 AC: 10 AN: 15062

Ashkenazi Jewish (ASJ) AF: 0.000292 AC: 1 AN: 3424

East Asian (EAS) AF: 0.000196 AC: 1 AN: 5108

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9690

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000956 AC: 64 AN: 66962

Other (OTH) AF: 0.000961 AC: 2 AN: 2082

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
6	-	-	Neuronopathy, distal hereditary motor, autosomal recessive 7 (6)
2	-	-	not provided (2)
1	-	-	Neuromuscular disease (1)
1	-	-	VWA1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.71
Mutation Taster		=29/171	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs749383814; hg19: chr1-1371178;