19-8580436-A-AC

Position:

• chr19-8580436-A-AC

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BS1_Supporting BS2

The NM_030957.4(ADAMTS10):​c.*456_*457insG variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.011 (10 hom., cov: 0)
  • Exomes 𝑓: 0.0026 (0 hom.)
• Consequence: ADAMTS10 NM_030957.4 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.262

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_benign. Variant got -5 ACMG points.

• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0112 (1572/140778) while in subpopulation AFR AF= 0.0147 (552/37576). AF 95% confidence interval is 0.0137. There are 10 homozygotes in gnomad4. There are 798 alleles in male gnomad4 subpopulation. Median coverage is 0. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADAMTS10	NM_030957.4	c.*456_*457insG		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	ENST00000597188.6	c.*456_*457insG		3_prime_UTR_variant	26/26	5	NM_030957.4	ENSP00000471851	P1
ADAMTS10	ENST00000270328.8	c.*456_*457insG		3_prime_UTR_variant	25/25	5		ENSP00000270328	P1
ADAMTS10	ENST00000595838.5	c.*456_*457insG		3_prime_UTR_variant	13/13	2		ENSP00000470501

Frequencies

GnomAD3 genomes AF: 0.0112 AC: 1570 AN: 140702 Hom.: 10 Cov.: 0

Gnomad AFR AF: 0.0146

Gnomad AMI AF: 0.0539

Gnomad AMR AF: 0.00573

Gnomad ASJ AF: 0.00541

Gnomad EAS AF: 0.00184

Gnomad SAS AF: 0.00589

Gnomad FIN AF: 0.0277

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00870

Gnomad OTH AF: 0.0106

GnomAD4 exome AF: 0.00263 AC: 29 AN: 11030 Hom.: 0 Cov.: 0 AF XY: 0.00206 AC XY: 13 AN XY: 6326

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00179

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00205

Gnomad4 FIN exome AF: 0.0139

Gnomad4 NFE exome AF: 0.00157

Gnomad4 OTH exome AF: 0.00598

GnomAD4 genome AF: 0.0112 AC: 1572 AN: 140778 Hom.: 10 Cov.: 0 AF XY: 0.0116 AC XY: 798 AN XY: 68636

Gnomad4 AFR AF: 0.0147

Gnomad4 AMR AF: 0.00573

Gnomad4 ASJ AF: 0.00541

Gnomad4 EAS AF: 0.00184

Gnomad4 SAS AF: 0.00568

Gnomad4 FIN AF: 0.0277

Gnomad4 NFE AF: 0.00868

Gnomad4 OTH AF: 0.0105

Bravo AF: 0.00991

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Weill-Marchesani syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

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: rs34057037; hg19: chr19-8645320;