19-8580654-A-AG

Position:

• chr19-8580654-A-AG

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_030957.4(ADAMTS10):​c.*238dupC variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.102 in 506,206 control chromosomes in the GnomAD database, including 2,958 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.096 (813 hom., cov: 29)
  • Exomes 𝑓: 0.10 (2145 hom.)
• Consequence: ADAMTS10 NM_030957.4 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.89

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 -16 ACMG points.

• BP6: Variant 19-8580654-A-AG is Benign according to our data. Variant chr19-8580654-A-AG is described in ClinVar as [Likely_benign]. Clinvar id is 330572.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.126 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADAMTS10	NM_030957.4	c.*238dupC		3_prime_UTR_variant	26/26	ENST00000597188.6	NP_112219.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADAMTS10	ENST00000597188	c.*238dupC		3_prime_UTR_variant	26/26	5	NM_030957.4	ENSP00000471851.1
ADAMTS10	ENST00000270328	c.*238dupC		3_prime_UTR_variant	25/25	5		ENSP00000270328.4
ADAMTS10	ENST00000595838	c.*238dupC		3_prime_UTR_variant	13/13	2		ENSP00000470501.1
ADAMTS10	ENST00000593913.5	n.*2427dupC		downstream_gene_variant		5		ENSP00000469901.1

Frequencies

GnomAD3 genomes AF: 0.0963 AC: 14551 AN: 151178 Hom.: 808 Cov.: 29

Gnomad AFR AF: 0.0445

Gnomad AMI AF: 0.0551

Gnomad AMR AF: 0.129

Gnomad ASJ AF: 0.0433

Gnomad EAS AF: 0.0598

Gnomad SAS AF: 0.0894

Gnomad FIN AF: 0.0919

Gnomad MID AF: 0.0633

Gnomad NFE AF: 0.128

Gnomad OTH AF: 0.0894

GnomAD4 exome AF: 0.105 AC: 37249 AN: 354908 Hom.: 2145 Cov.: 1 AF XY: 0.103 AC XY: 19480 AN XY: 189260

Gnomad4 AFR exome AF: 0.0412

Gnomad4 AMR exome AF: 0.140

Gnomad4 ASJ exome AF: 0.0461

Gnomad4 EAS exome AF: 0.0532

Gnomad4 SAS exome AF: 0.0854

Gnomad4 FIN exome AF: 0.0931

Gnomad4 NFE exome AF: 0.120

Gnomad4 OTH exome AF: 0.0984

GnomAD4 genome AF: 0.0963 AC: 14569 AN: 151298 Hom.: 813 Cov.: 29 AF XY: 0.0946 AC XY: 6996 AN XY: 73918

Gnomad4 AFR AF: 0.0445

Gnomad4 AMR AF: 0.130

Gnomad4 ASJ AF: 0.0433

Gnomad4 EAS AF: 0.0590

Gnomad4 SAS AF: 0.0897

Gnomad4 FIN AF: 0.0919

Gnomad4 NFE AF: 0.128

Gnomad4 OTH AF: 0.0885

Bravo AF: 0.0945

Asia WGS AF: 0.0700 AC: 245 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Weill-Marchesani syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 31, 2018

- -

Computational scores

Source: dbNSFP v4.3

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: rs151216219; hg19: chr19-8645538;