5-179130005-C-T

Variant names:

• chr5-179130005-C-T
• rs137853147
• NM_014244.5:c.2384G>A

Variant summary

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

The NM_014244.5(ADAMTS2):​c.2384G>A​(p.Trp795*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 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 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 7.79
• Publications: 4 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 5-179130005-C-T is Pathogenic according to our data. Variant chr5-179130005-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 5503.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.2384G>A	p.Trp795*	stop_gained	Exon 16 of 22	ENST00000251582.12	NP_055059.2
ADAMTS2	XM_047417895.1	c.1889G>A	p.Trp630*	stop_gained	Exon 15 of 21		XP_047273851.1
ADAMTS2	XM_047417896.1	c.1502G>A	p.Trp501*	stop_gained	Exon 14 of 20		XP_047273852.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADAMTS2	ENST00000251582.12	c.2384G>A	p.Trp795*	stop_gained	Exon 16 of 22	1	NM_014244.5	ENSP00000251582.7
ADAMTS2	ENST00000518335.3	c.2384G>A	p.Trp795*	stop_gained	Exon 16 of 21	3		ENSP00000489888.2
ADAMTS2	ENST00000698889.1	n.2384G>A		non_coding_transcript_exon_variant	Exon 16 of 21			ENSP00000514008.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

Submissions by phenotype

Ehlers-Danlos syndrome, dermatosparaxis type Pathogenic:2

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.

Aug 01, 1999

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.66
CADD	Pathogenic	44
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0	.;.
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.0	.;.
MetaRNN	Benign	0.0	.;.
MutationAssessor	Benign	0.0	.;.
PhyloP100		7.8
PROVEAN	Benign	0.0	.;.
REVEL	Benign	0.0
Sift	Pathogenic	0.0	.;.
Sift4G	Pathogenic	0.0	.;.
Vest4		0.90
GERP RS		5.0
Mutation Taster		=6/194	disease causing (ClinVar)

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: rs137853147; hg19: chr5-178557006;