19-8580873-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_030957.4(ADAMTS10):c.*20G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000707 in 1,577,292 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0036 (6 hom., cov: 31)
  • Exomes 𝑓: 0.00039 (3 hom.)
• Consequence: ADAMTS10 NM_030957.4 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0780

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).
• BP6: Variant 19-8580873-C-T is Benign according to our data. Variant chr19-8580873-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 893868.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00364 (554/152220) while in subpopulation AFR AF= 0.0127 (526/41554). AF 95% confidence interval is 0.0118. There are 6 homozygotes in gnomad4. There are 273 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADAMTS10	NM_030957.4	c.*20G>A		3_prime_UTR_variant	26/26	ENST00000597188.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADAMTS10	ENST00000597188.6	c.*20G>A		3_prime_UTR_variant	26/26	5	NM_030957.4	P1
ADAMTS10	ENST00000270328.8	c.*20G>A		3_prime_UTR_variant	25/25	5		P1
ADAMTS10	ENST00000595838.5	c.*20G>A		3_prime_UTR_variant	13/13	2
ADAMTS10	ENST00000593913.5	c.*2209G>A		3_prime_UTR_variant, NMD_transcript_variant	22/22	5

Frequencies

GnomAD3 genomes AF: 0.00365 AC: 555 AN: 152102 Hom.: 6 Cov.: 31

Gnomad AFR AF: 0.0127

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00103 AC: 208 AN: 202680 Hom.: 3 AF XY: 0.000836 AC XY: 93 AN XY: 111210

Gnomad AFR exome AF: 0.0155

Gnomad AMR exome AF: 0.000763

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000730

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000571

Gnomad OTH exome AF: 0.000576

GnomAD4 exome AF: 0.000394 AC: 561 AN: 1425072 Hom.: 3 Cov.: 28 AF XY: 0.000331 AC XY: 234 AN XY: 707924

Gnomad4 AFR exome AF: 0.0131

Gnomad4 AMR exome AF: 0.000783

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000264

Gnomad4 SAS exome AF: 0.0000600

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000202

Gnomad4 OTH exome AF: 0.00120

GnomAD4 genome AF: 0.00364 AC: 554 AN: 152220 Hom.: 6 Cov.: 31 AF XY: 0.00367 AC XY: 273 AN XY: 74420

Gnomad4 AFR AF: 0.0127

Gnomad4 AMR AF: 0.00131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00167 Hom.: 0

Bravo AF: 0.00396

Asia WGS AF: 0.00144 AC: 5 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

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. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

May 11, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
Cadd	Benign	15
Dann	Benign	0.92

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: rs137928083; hg19: chr19-8645757;