chr19-8580444-C-G

Position:

• chr19-8580444-C-G

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.*449G>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0143 in 171,314 control chromosomes in the GnomAD database, including 33 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (28 hom., cov: 30)
  • Exomes 𝑓: 0.011 (5 hom.)
• Consequence: ADAMTS10 NM_030957.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.10

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=-0.98).
• BP6: Variant 19-8580444-C-G is Benign according to our data. Variant chr19-8580444-C-G is described in ClinVar as [Benign]. Clinvar id is 330568.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0147 (2227/151820) while in subpopulation AMR AF= 0.0236 (360/15270). AF 95% confidence interval is 0.0216. There are 28 homozygotes in gnomad4. There are 1035 alleles in male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 28 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADAMTS10	NM_030957.4	c.*449G>C		3_prime_UTR_variant	26/26	ENST00000597188.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADAMTS10	ENST00000597188.6	c.*449G>C		3_prime_UTR_variant	26/26	5	NM_030957.4	P1
ADAMTS10	ENST00000270328.8	c.*449G>C		3_prime_UTR_variant	25/25	5		P1
ADAMTS10	ENST00000595838.5	c.*449G>C		3_prime_UTR_variant	13/13	2

Frequencies

GnomAD3 genomes AF: 0.0147 AC: 2229 AN: 151702 Hom.: 28 Cov.: 30

Gnomad AFR AF: 0.00417

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0237

Gnomad ASJ AF: 0.0104

Gnomad EAS AF: 0.0200

Gnomad SAS AF: 0.00560

Gnomad FIN AF: 0.00915

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0201

Gnomad OTH AF: 0.0292

GnomAD4 exome AF: 0.0113 AC: 220 AN: 19494 Hom.: 5 Cov.: 0 AF XY: 0.00989 AC XY: 110 AN XY: 11126

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0175

Gnomad4 ASJ exome AF: 0.0137

Gnomad4 EAS exome AF: 0.0114

Gnomad4 SAS exome AF: 0.00298

Gnomad4 FIN exome AF: 0.0113

Gnomad4 NFE exome AF: 0.0137

Gnomad4 OTH exome AF: 0.00996

GnomAD4 genome AF: 0.0147 AC: 2227 AN: 151820 Hom.: 28 Cov.: 30 AF XY: 0.0139 AC XY: 1035 AN XY: 74240

Gnomad4 AFR AF: 0.00416

Gnomad4 AMR AF: 0.0236

Gnomad4 ASJ AF: 0.0104

Gnomad4 EAS AF: 0.0199

Gnomad4 SAS AF: 0.00560

Gnomad4 FIN AF: 0.00915

Gnomad4 NFE AF: 0.0201

Gnomad4 OTH AF: 0.0289

Alfa AF: 0.00310 Hom.: 1

Bravo AF: 0.0157

Asia WGS AF: 0.0130 AC: 44 AN: 3478

ClinVar

Significance: 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 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 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

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	0.66
DANN	Benign	0.22

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: rs555471852; hg19: chr19-8645328; COSMIC: COSV54354186; COSMIC: COSV54354186;