rs10418929

Positions:

• chr19-8586198-C-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The NM_030957.4(ADAMTS10):​c.2584G>T​(p.Ala862Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00594 in 1,611,990 control chromosomes in the GnomAD database, including 435 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.030 (237 hom., cov: 33)
  • Exomes 𝑓: 0.0034 (198 hom.)
• Consequence: ADAMTS10 NM_030957.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 2.17

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 Benign. Variant got -19 ACMG points.

• 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0016127229).
• BP6: Variant 19-8586198-C-A is Benign according to our data. Variant chr19-8586198-C-A is described in ClinVar as [Benign]. Clinvar id is 330582.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-8586198-C-A is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0993 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADAMTS10	NM_030957.4	c.2584G>T	p.Ala862Ser	missense_variant	22/26	ENST00000597188.6	NP_112219.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADAMTS10	ENST00000597188.6	c.2584G>T	p.Ala862Ser	missense_variant	22/26	5	NM_030957.4	ENSP00000471851.1

Frequencies

GnomAD3 genomes AF: 0.0301 AC: 4587 AN: 152172 Hom.: 236 Cov.: 33

Gnomad AFR AF: 0.102

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0132

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.0139

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000632

Gnomad OTH AF: 0.0191

GnomAD3 exomes AF: 0.00910 AC: 2256 AN: 247826 Hom.: 78 AF XY: 0.00719 AC XY: 969 AN XY: 134726

Gnomad AFR exome AF: 0.104

Gnomad AMR exome AF: 0.00613

Gnomad ASJ exome AF: 0.00130

Gnomad EAS exome AF: 0.0134

Gnomad SAS exome AF: 0.000295

Gnomad FIN exome AF: 0.0000953

Gnomad NFE exome AF: 0.000815

Gnomad OTH exome AF: 0.00627

GnomAD4 exome AF: 0.00341 AC: 4979 AN: 1459700 Hom.: 198 Cov.: 32 AF XY: 0.00311 AC XY: 2256 AN XY: 726178

Gnomad4 AFR exome AF: 0.102

Gnomad4 AMR exome AF: 0.00669

Gnomad4 ASJ exome AF: 0.00169

Gnomad4 EAS exome AF: 0.00635

Gnomad4 SAS exome AF: 0.000406

Gnomad4 FIN exome AF: 0.0000761

Gnomad4 NFE exome AF: 0.000321

Gnomad4 OTH exome AF: 0.00820

GnomAD4 genome AF: 0.0302 AC: 4599 AN: 152290 Hom.: 237 Cov.: 33 AF XY: 0.0300 AC XY: 2232 AN XY: 74456

Gnomad4 AFR AF: 0.102

Gnomad4 AMR AF: 0.0132

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.0135

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.000632

Gnomad4 OTH AF: 0.0189

Alfa AF: 0.0173 Hom.: 52

Bravo AF: 0.0348

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.0949 AC: 418

ESP6500EA AF: 0.000814 AC: 7

ExAC AF: 0.0103 AC: 1255

Asia WGS AF: 0.0140 AC: 50 AN: 3478

EpiCase AF: 0.000654

EpiControl AF: 0.00154

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 16, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Weill-Marchesani syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	20
DANN	Benign	0.89
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.26
FATHMM_MKL	Benign	0.56	D
LIST_S2	Benign	0.56	T;T;.
MetaRNN	Benign	0.0016	T;T;T
MetaSVM	Benign	-1.1	T
PrimateAI	Benign	0.47	T
PROVEAN	Benign	0.88	.;N;.
REVEL	Benign	0.078
Sift	Benign	0.71	.;T;.
Sift4G	Benign	0.43	T;T;T
Vest4		0.073
MPC		1.3
ClinPred		0.0044	T
GERP RS		4.1
gMVP		0.27

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs10418929; hg19: chr19-8651082;