rs28567966

chr15-100152640-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_139057.4(ADAMTS17):c.1445T>C(p.Met482Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.149 in 1,613,936 control chromosomes in the GnomAD database, including 18,976 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar.

• Frequency:
  • Genomes: 𝑓 0.16 (2015 hom., cov: 32)
  • Exomes 𝑓: 0.15 (16961 hom.)
• Consequence: ADAMTS17 NM_139057.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 2.60

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0036643445).
• BP6: Variant 15-100152640-A-G is Benign according to our data. Variant chr15-100152640-A-G is described in ClinVar as [Benign]. Clinvar id is 315290.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-100152640-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.198 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADAMTS17	NM_139057.4	c.1445T>C	p.Met482Thr	missense_variant	10/22	ENST00000268070.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADAMTS17	ENST00000268070.9	c.1445T>C	p.Met482Thr	missense_variant	10/22	1	NM_139057.4
ADAMTS17	ENST00000568565.2	c.1445T>C	p.Met482Thr	missense_variant	10/23	5		P1
ADAMTS17	ENST00000378898.8	n.1126T>C		non_coding_transcript_exon_variant	9/15	2

Frequencies

GnomAD3 genomes AF: 0.156 AC: 23663 AN: 152016 Hom.: 2008 Cov.: 32

Gnomad AFR AF: 0.201

Gnomad AMI AF: 0.206

Gnomad AMR AF: 0.115

Gnomad ASJ AF: 0.222

Gnomad EAS AF: 0.0592

Gnomad SAS AF: 0.184

Gnomad FIN AF: 0.0862

Gnomad MID AF: 0.172

Gnomad NFE AF: 0.149

Gnomad OTH AF: 0.164

GnomAD3 exomes AF: 0.141 AC: 35439 AN: 251380 Hom.: 2855 AF XY: 0.145 AC XY: 19744 AN XY: 135862

Gnomad AFR exome AF: 0.209

Gnomad AMR exome AF: 0.0848

Gnomad ASJ exome AF: 0.220

Gnomad EAS exome AF: 0.0558

Gnomad SAS exome AF: 0.195

Gnomad FIN exome AF: 0.0914

Gnomad NFE exome AF: 0.149

Gnomad OTH exome AF: 0.153

GnomAD4 exome AF: 0.148 AC: 216343 AN: 1461802 Hom.: 16961 Cov.: 41 AF XY: 0.150 AC XY: 109272 AN XY: 727202

Gnomad4 AFR exome AF: 0.209

Gnomad4 AMR exome AF: 0.0879

Gnomad4 ASJ exome AF: 0.219

Gnomad4 EAS exome AF: 0.0606

Gnomad4 SAS exome AF: 0.197

Gnomad4 FIN exome AF: 0.0960

Gnomad4 NFE exome AF: 0.148

Gnomad4 OTH exome AF: 0.156

GnomAD4 genome AF: 0.156 AC: 23694 AN: 152134 Hom.: 2015 Cov.: 32 AF XY: 0.152 AC XY: 11322 AN XY: 74398

Gnomad4 AFR AF: 0.201

Gnomad4 AMR AF: 0.115

Gnomad4 ASJ AF: 0.222

Gnomad4 EAS AF: 0.0594

Gnomad4 SAS AF: 0.185

Gnomad4 FIN AF: 0.0862

Gnomad4 NFE AF: 0.149

Gnomad4 OTH AF: 0.162

Alfa AF: 0.151 Hom.: 2876

Bravo AF: 0.159

TwinsUK AF: 0.156 AC: 579

ALSPAC AF: 0.153 AC: 590

ESP6500AA AF: 0.200 AC: 881

ESP6500EA AF: 0.149 AC: 1279

ExAC AF: 0.146 AC: 17675

Asia WGS AF: 0.111 AC: 389 AN: 3478

EpiCase AF: 0.151

EpiControl AF: 0.151

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Weill-Marchesani 4 syndrome, recessive Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 04, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.041
BayesDel_addAF	Benign	-0.81	T
BayesDel_noAF	Benign	-0.79
Cadd	Benign	6.9
Dann	Benign	0.29
DEOGEN2	Benign	0.016	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.76
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.057	T
MetaRNN	Benign	0.0037	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-1.7	N
MutationTaster	Benign	1.0	P
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	2.1	N
REVEL	Benign	0.029
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.10
MPC		0.11
ClinPred		0.0012	T
GERP RS		2.6
Varity_R		0.036
gMVP		0.36

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: rs28567966; hg19: chr15-100692845; COSMIC: COSV51478380;