rs28567966

Variant names:

• chr15-100152640-A-G
• rs28567966
• NM_139057.4:c.1445T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000268070.9(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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M482I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.16 (2015 hom., cov: 32)
  • Exomes 𝑓: 0.15 (16961 hom.)
• Consequence: ADAMTS17 ENST00000268070.9 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 2.60
• Publications: 22 publications found

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]

ADAMTS17 Gene-Disease associations (from GenCC):

• Weill-Marchesani 4 syndrome, recessive

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae), G2P, Illumina

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 315290.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.198 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000268070.9. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAMTS17	NM_139057.4	MANE Select	c.1445T>C	p.Met482Thr	missense	Exon 10 of 22	NP_620688.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAMTS17	ENST00000268070.9	TSL:1 MANE Select	c.1445T>C	p.Met482Thr	missense	Exon 10 of 22	ENSP00000268070.4
	ADAMTS17	ENST00000568565.2	TSL:5	c.1445T>C	p.Met482Thr	missense	Exon 10 of 23	ENSP00000456161.2
	ADAMTS17	ENST00000378898.8	TSL:2	n.1126T>C		non_coding_transcript_exon	Exon 9 of 15

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

GnomAD2 exomes AF: 0.141 AC: 35439 AN: 251380 AF XY: 0.145

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 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

African (AFR) AF: 0.209 AC: 6997 AN: 33478

American (AMR) AF: 0.0879 AC: 3930 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.219 AC: 5711 AN: 26136

East Asian (EAS) AF: 0.0606 AC: 2407 AN: 39700

South Asian (SAS) AF: 0.197 AC: 16957 AN: 86258

European-Finnish (FIN) AF: 0.0960 AC: 5124 AN: 53348

Middle Eastern (MID) AF: 0.226 AC: 1301 AN: 5766

European-Non Finnish (NFE) AF: 0.148 AC: 164469 AN: 1112000

Other (OTH) AF: 0.156 AC: 9447 AN: 60394

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

African (AFR) AF: 0.201 AC: 8353 AN: 41486

American (AMR) AF: 0.115 AC: 1753 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.222 AC: 770 AN: 3468

East Asian (EAS) AF: 0.0594 AC: 307 AN: 5170

South Asian (SAS) AF: 0.185 AC: 890 AN: 4822

European-Finnish (FIN) AF: 0.0862 AC: 914 AN: 10598

Middle Eastern (MID) AF: 0.178 AC: 52 AN: 292

European-Non Finnish (NFE) AF: 0.149 AC: 10127 AN: 67996

Other (OTH) AF: 0.162 AC: 341 AN: 2106

Alfa AF: 0.152 Hom.: 6024

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

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Weill-Marchesani 4 syndrome, recessive (2)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		2.6
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
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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