rs4476282

Variant names:

• chr19-8586678-A-G
• rs4476282
• NM_030957.4:c.2283T>C

Your query was ambiguous. Multiple possible variants found:

• chr19-8586678-A-G
• chr19-8586678-A-T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_030957.4(ADAMTS10):​c.2283T>C​(p.Pro761Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.213 in 1,613,782 control chromosomes in the GnomAD database, including 37,409 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P761P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.22 (3738 hom., cov: 32)
  • Exomes 𝑓: 0.21 (33671 hom.)
• Consequence: ADAMTS10 NM_030957.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -2.86
• Publications: 15 publications found

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]

ADAMTS10 Gene-Disease associations (from GenCC):

• Weill-Marchesani syndrome 1

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• Weill-Marchesani syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 19-8586678-A-G is Benign according to our data. Variant chr19-8586678-A-G is described in ClinVar as Benign. ClinVar VariationId is 330587.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.86 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.219 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADAMTS10	NM_030957.4	c.2283T>C	p.Pro761Pro	synonymous_variant	Exon 20 of 26	ENST00000597188.6	NP_112219.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADAMTS10	ENST00000597188.6	c.2283T>C	p.Pro761Pro	synonymous_variant	Exon 20 of 26	5	NM_030957.4	ENSP00000471851.1

Frequencies

GnomAD3 genomes AF: 0.220 AC: 33350 AN: 151868 Hom.: 3740 Cov.: 32

Gnomad AFR AF: 0.223

Gnomad AMI AF: 0.112

Gnomad AMR AF: 0.206

Gnomad ASJ AF: 0.193

Gnomad EAS AF: 0.116

Gnomad SAS AF: 0.145

Gnomad FIN AF: 0.319

Gnomad MID AF: 0.247

Gnomad NFE AF: 0.221

Gnomad OTH AF: 0.217

GnomAD2 exomes AF: 0.213 AC: 53351 AN: 250704 AF XY: 0.207

Gnomad AFR exome AF: 0.218

Gnomad AMR exome AF: 0.243

Gnomad ASJ exome AF: 0.213

Gnomad EAS exome AF: 0.112

Gnomad FIN exome AF: 0.304

Gnomad NFE exome AF: 0.223

Gnomad OTH exome AF: 0.220

GnomAD4 exome AF: 0.212 AC: 310219 AN: 1461794 Hom.: 33671 Cov.: 36 AF XY: 0.210 AC XY: 152699 AN XY: 727214

African (AFR) AF: 0.229 AC: 7678 AN: 33480

American (AMR) AF: 0.238 AC: 10623 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.209 AC: 5475 AN: 26134

East Asian (EAS) AF: 0.135 AC: 5358 AN: 39700

South Asian (SAS) AF: 0.130 AC: 11250 AN: 86258

European-Finnish (FIN) AF: 0.302 AC: 16106 AN: 53336

Middle Eastern (MID) AF: 0.225 AC: 1298 AN: 5768

European-Non Finnish (NFE) AF: 0.216 AC: 240241 AN: 1112002

Other (OTH) AF: 0.202 AC: 12190 AN: 60392

GnomAD4 genome AF: 0.220 AC: 33369 AN: 151988 Hom.: 3738 Cov.: 32 AF XY: 0.220 AC XY: 16356 AN XY: 74288

African (AFR) AF: 0.223 AC: 9231 AN: 41454

American (AMR) AF: 0.206 AC: 3139 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.193 AC: 671 AN: 3468

East Asian (EAS) AF: 0.117 AC: 604 AN: 5168

South Asian (SAS) AF: 0.144 AC: 693 AN: 4818

European-Finnish (FIN) AF: 0.319 AC: 3371 AN: 10564

Middle Eastern (MID) AF: 0.245 AC: 72 AN: 294

European-Non Finnish (NFE) AF: 0.221 AC: 15021 AN: 67938

Other (OTH) AF: 0.220 AC: 465 AN: 2110

Alfa AF: 0.217 Hom.: 6474

Bravo AF: 0.211

Asia WGS AF: 0.173 AC: 602 AN: 3478

EpiCase AF: 0.220

EpiControl AF: 0.221

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Apr 19, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not specified Benign:2

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Weill-Marchesani syndrome Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
BayesDel_noAF	Benign	-0.76
CADD	Benign	0.077
DANN	Benign	0.50
PhyloP100		-2.9
Mutation Taster		=100/0	polymorphism (auto)

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: rs4476282; hg19: chr19-8651562; COSMIC: COSV54352908; COSMIC: COSV54352908;