chr19-8580722-C-T

Position:

• chr19-8580722-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.*171G>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 0.0113 in 604,506 control chromosomes in the GnomAD database, including 52 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0099 (11 hom., cov: 31)
  • Exomes 𝑓: 0.012 (41 hom.)
• Consequence: ADAMTS10 NM_030957.4 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.280

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=-0.78).
• BP6: Variant 19-8580722-C-T is Benign according to our data. Variant chr19-8580722-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 893579.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00992 (1508/152080) while in subpopulation NFE AF= 0.0141 (955/67932). AF 95% confidence interval is 0.0133. There are 11 homozygotes in gnomad4. There are 754 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 11 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADAMTS10	NM_030957.4	c.*171G>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.*171G>A		3_prime_UTR_variant	26/26	5	NM_030957.4	P1
ADAMTS10	ENST00000270328.8	c.*171G>A		3_prime_UTR_variant	25/25	5		P1
ADAMTS10	ENST00000595838.5	c.*171G>A		3_prime_UTR_variant	13/13	2
ADAMTS10	ENST00000593913.5	c.*2360G>A		3_prime_UTR_variant, NMD_transcript_variant	22/22	5

Frequencies

GnomAD3 genomes AF: 0.00992 AC: 1507 AN: 151962 Hom.: 11 Cov.: 31

Gnomad AFR AF: 0.00290

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0113

Gnomad ASJ AF: 0.00576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00518

Gnomad FIN AF: 0.0170

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0141

Gnomad OTH AF: 0.0124

GnomAD4 exome AF: 0.0118 AC: 5323 AN: 452426 Hom.: 41 Cov.: 5 AF XY: 0.0117 AC XY: 2829 AN XY: 241162

Gnomad4 AFR exome AF: 0.00381

Gnomad4 AMR exome AF: 0.0118

Gnomad4 ASJ exome AF: 0.00628

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00813

Gnomad4 FIN exome AF: 0.0131

Gnomad4 NFE exome AF: 0.0140

Gnomad4 OTH exome AF: 0.0134

GnomAD4 genome AF: 0.00992 AC: 1508 AN: 152080 Hom.: 11 Cov.: 31 AF XY: 0.0101 AC XY: 754 AN XY: 74352

Gnomad4 AFR AF: 0.00294

Gnomad4 AMR AF: 0.0112

Gnomad4 ASJ AF: 0.00576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00519

Gnomad4 FIN AF: 0.0170

Gnomad4 NFE AF: 0.0141

Gnomad4 OTH AF: 0.0123

Alfa AF: 0.0109 Hom.: 2

Bravo AF: 0.00966

Asia WGS AF: 0.00491 AC: 17 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 20, 2018	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Weill-Marchesani syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	6.9
DANN	Benign	0.58

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: rs79238375; hg19: chr19-8645606;