19-8580807-G-GC

Position:

• chr19-8580807-G-GC

Variant summary

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

The NM_030957.4(ADAMTS10):​c.*85_*86insG variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00355 in 1,091,496 control chromosomes in the GnomAD database, including 12 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.0030 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0036 (12 hom.)
• Consequence: ADAMTS10 NM_030957.4 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.200

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 nfe. gnomad4 allele frequency = 0.00303 (460/151792) while in subpopulation NFE AF= 0.0054 (366/67824). AF 95% confidence interval is 0.00494. There are 0 homozygotes in gnomad4. There are 206 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 12 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADAMTS10	NM_030957.4	c.*85_*86insG		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.*85_*86insG		3_prime_UTR_variant	26/26	5	NM_030957.4	ENSP00000471851	P1
ADAMTS10	ENST00000270328.8	c.*85_*86insG		3_prime_UTR_variant	25/25	5		ENSP00000270328	P1
ADAMTS10	ENST00000595838.5	c.*85_*86insG		3_prime_UTR_variant	13/13	2		ENSP00000470501
ADAMTS10	ENST00000593913.5	c.*2274_*2275insG		3_prime_UTR_variant, NMD_transcript_variant	22/22	5		ENSP00000469901

Frequencies

GnomAD3 genomes AF: 0.00303 AC: 460 AN: 151676 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000630

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00530

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00540

Gnomad OTH AF: 0.000961

GnomAD4 exome AF: 0.00363 AC: 3414 AN: 939704 Hom.: 12 Cov.: 13 AF XY: 0.00346 AC XY: 1660 AN XY: 479570

Gnomad4 AFR exome AF: 0.000990

Gnomad4 AMR exome AF: 0.000316

Gnomad4 ASJ exome AF: 0.0000959

Gnomad4 EAS exome AF: 0.000121

Gnomad4 SAS exome AF: 0.000904

Gnomad4 FIN exome AF: 0.00495

Gnomad4 NFE exome AF: 0.00446

Gnomad4 OTH exome AF: 0.00227

GnomAD4 genome AF: 0.00303 AC: 460 AN: 151792 Hom.: 0 Cov.: 31 AF XY: 0.00278 AC XY: 206 AN XY: 74176

Gnomad4 AFR AF: 0.000628

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00530

Gnomad4 NFE AF: 0.00540

Gnomad4 OTH AF: 0.000951

Bravo AF: 0.00247

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Weill-Marchesani syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Nov 01, 2022

- -

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: rs576948646; hg19: chr19-8645691;