15-99971842-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_139057.4(ADAMTS17):c.*2560T>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 0.38 in 152,218 control chromosomes in the GnomAD database, including 12,357 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.38 (12353 hom., cov: 34)
  • Exomes 𝑓: 0.61 (4 hom.)
• Consequence: ADAMTS17 NM_139057.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0530

Genes affected

ADAMTS17 (HGNC:17109): (ADAM metallopeptidase with thrombospondin type 1 motif 17) This gene encodes a member of the ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) protein family. ADAMTS family members share several distinct protein modules, including a propeptide region, a metalloproteinase domain, a disintegrin-like domain, and a thrombospondin type 1 (TS) motif. Individual members of this family differ in the number of C-terminal TS motifs, and some have unique C-terminal domains. The encoded preproprotein is proteolytically processed to generate the mature protein, which may promote breast cancer cell growth and survival. Mutations in this gene are associated with a Weill-Marchesani-like syndrome, which is characterized by lenticular myopia, ectopia lentis, glaucoma, spherophakia, and short stature. [provided by RefSeq, May 2016]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 15-99971842-A-G is Benign according to our data. Variant chr15-99971842-A-G is described in ClinVar as [Benign]. Clinvar id is 315136.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.477 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADAMTS17	NM_139057.4	c.*2560T>C		3_prime_UTR_variant	22/22	ENST00000268070.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADAMTS17	ENST00000268070.9	c.*2560T>C		3_prime_UTR_variant	22/22	1	NM_139057.4
	ENST00000528696.3	n.142-846A>G		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.380 AC: 57821 AN: 152080 Hom.: 12358 Cov.: 34

Gnomad AFR AF: 0.179

Gnomad AMI AF: 0.589

Gnomad AMR AF: 0.347

Gnomad ASJ AF: 0.485

Gnomad EAS AF: 0.435

Gnomad SAS AF: 0.372

Gnomad FIN AF: 0.484

Gnomad MID AF: 0.372

Gnomad NFE AF: 0.482

Gnomad OTH AF: 0.389

GnomAD4 exome AF: 0.611 AC: 11 AN: 18 Hom.: 4 Cov.: 0 AF XY: 0.714 AC XY: 10 AN XY: 14

Gnomad4 AFR exome AF: 0.500

Gnomad4 FIN exome AF: 0.500

Gnomad4 NFE exome AF: 0.643

GnomAD4 genome AF: 0.380 AC: 57815 AN: 152200 Hom.: 12353 Cov.: 34 AF XY: 0.380 AC XY: 28304 AN XY: 74394

Gnomad4 AFR AF: 0.179

Gnomad4 AMR AF: 0.347

Gnomad4 ASJ AF: 0.485

Gnomad4 EAS AF: 0.435

Gnomad4 SAS AF: 0.371

Gnomad4 FIN AF: 0.484

Gnomad4 NFE AF: 0.482

Gnomad4 OTH AF: 0.387

Alfa AF: 0.462 Hom.: 16327

Bravo AF: 0.363

Asia WGS AF: 0.341 AC: 1186 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Weill-Marchesani 4 syndrome, recessive 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
Cadd	Benign	0.17
Dann	Benign	0.36

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs10468183; hg19: chr15-100512047;