rs267606637

Positions:

• chr19-8589302-C-A
• chr19-8589302-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PP2 PP3_Strong PP5

The NM_030957.4(ADAMTS10):​c.2098G>T​(p.Gly700Cys) variant causes a missense 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. 11/19 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 31)
• Consequence: ADAMTS10 NM_030957.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.82

Genes affected

ADAMTS10 (HGNC:13201): (ADAM metallopeptidase with thrombospondin type 1 motif 10) This gene belongs to the ADAMTS (a disintegrin and metalloproteinase domain with thrombospondin type-1 motifs) family of zinc-dependent proteases. ADAMTS proteases are complex secreted enzymes containing a prometalloprotease domain of the reprolysin type attached to an ancillary domain with a highly conserved structure that includes at least one thrombospondin type 1 repeat. They have been demonstrated to have important roles in connective tissue organization, coagulation, inflammation, arthritis, angiogenesis and cell migration. The product of this gene plays a major role in growth and in skin, lens, and heart development. It is also a candidate gene for autosomal recessive Weill-Marchesani syndrome. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), ADAMTS10. . Gene score misZ 3.628 (greater than the threshold 3.09). Trascript score misZ 3.793 (greater than threshold 3.09). GenCC has associacion of gene with Weill-Marchesani syndrome 1, Weill-Marchesani syndrome.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.99
• PP5: Variant 19-8589302-C-A is Pathogenic according to our data. Variant chr19-8589302-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 1950.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADAMTS10	NM_030957.4	c.2098G>T	p.Gly700Cys	missense_variant	18/26	ENST00000597188.6	NP_112219.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADAMTS10	ENST00000597188.6	c.2098G>T	p.Gly700Cys	missense_variant	18/26	5	NM_030957.4	ENSP00000471851	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Weill-Marchesani syndrome 1 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 01, 2009

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
CADD	Pathogenic	26
DANN	Uncertain	1.0
Eigen	Pathogenic	0.76
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D;D;.
M_CAP	Pathogenic	0.39	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Uncertain	0.74	D
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-8.4	.;D;.
REVEL	Pathogenic	0.85
Sift	Uncertain	0.0010	.;D;.
Sift4G	Pathogenic	0.0	D;D;D
Vest4		0.94
MutPred		0.89		.;Loss of disorder (P = 0.068);Loss of disorder (P = 0.068);
MVP		0.92
MPC		1.7
ClinPred		1.0	D
GERP RS		5.2
gMVP		0.99

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

Publications

LitVar

Other links and lift over

dbSNP: rs267606637; hg19: chr19-8654186;