rs1057517277

Variant names:

• chr5-179128117-ACCTGTGC-A
• rs1057517277
• NM_014244.5:c.2458-6_2458delGCACAGG

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_014244.5(ADAMTS2):​c.2458-6_2458delGCACAGG​(p.Val820fs) variant causes a frameshift, splice acceptor, splice region, intron change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ADAMTS2 NM_014244.5 frameshift, splice_acceptor, splice_region, intron
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 6.63
• Publications: 1 publications found

Genes affected

ADAMTS2 (HGNC:218): (ADAM metallopeptidase with thrombospondin type 1 motif 2) This gene encodes a member of the ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) protein family. Members of the family share several distinct protein modules, including a propeptide region, a metalloproteinase domain, a disintegrin-like domain, and a thrombospondin type 1 (TS) motif. Individual members of this family differ in the number of C-terminal TS motifs, and some have unique C-terminal domains. The encoded preproprotein is proteolytically processed to generate the mature procollagen N-proteinase. This proteinase excises the N-propeptide of the fibrillar procollagens types I-III and type V. Mutations in this gene cause Ehlers-Danlos syndrome type VIIC, a recessively inherited connective-tissue disorder. Alternative splicing results in multiple transcript variants, at least one of which encodes an isoform that is proteolytically processed. [provided by RefSeq, Feb 2016]

ADAMTS2 Gene-Disease associations (from GenCC):

• Ehlers-Danlos syndrome, dermatosparaxis type

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet, G2P, PanelApp Australia, Illumina

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-179128117-ACCTGTGC-A is Pathogenic according to our data. Variant chr5-179128117-ACCTGTGC-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 371445.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADAMTS2	NM_014244.5	c.2458-6_2458delGCACAGG	p.Val820fs	frameshift_variant, splice_acceptor_variant, splice_region_variant, intron_variant	Exon 17 of 22	ENST00000251582.12	NP_055059.2
ADAMTS2	XM_047417895.1	c.1963-6_1963delGCACAGG	p.Val655fs	frameshift_variant, splice_acceptor_variant, splice_region_variant, intron_variant	Exon 16 of 21		XP_047273851.1
ADAMTS2	XM_047417896.1	c.1576-6_1576delGCACAGG	p.Val526fs	frameshift_variant, splice_acceptor_variant, splice_region_variant, intron_variant	Exon 15 of 20		XP_047273852.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADAMTS2	ENST00000251582.12	c.2458-6_2458delGCACAGG	p.Val820fs	frameshift_variant, splice_acceptor_variant, splice_region_variant, intron_variant	Exon 17 of 22	1	NM_014244.5	ENSP00000251582.7
ADAMTS2	ENST00000518335.3	c.2458-6_2458delGCACAGG	p.Val820fs	frameshift_variant, splice_acceptor_variant, splice_region_variant, intron_variant	Exon 17 of 21	3		ENSP00000489888.2
ADAMTS2	ENST00000698889.1	n.2458-6_2458delGCACAGG		splice_acceptor_variant, splice_region_variant, intron_variant, non_coding_transcript_exon_variant	Exon 17 of 21			ENSP00000514008.1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Ehlers-Danlos syndrome, dermatosparaxis type Pathogenic:1

Oct 18, 2016

Counsyl

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.6
Mutation Taster		=6/194	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs1057517277; hg19: chr5-178555118;