rs2573652

Variant names:

• chr15-99974409-T-C
• rs2573652
• NM_139057.4:c.3281A>G

Your query was ambiguous. Multiple possible variants found:

• chr15-99974409-T-C
• chr15-99974409-T-G

Variant summary

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

The NM_139057.4(ADAMTS17):​c.3281A>G​(p.Asn1094Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.667 in 1,613,878 control chromosomes in the GnomAD database, including 362,029 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.70 (37672 hom., cov: 33)
  • Exomes 𝑓: 0.66 (324357 hom.)
• Consequence: ADAMTS17 NM_139057.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 2.56
• Publications: 51 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

ENSG00000259363 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=8.221907E-7).
• BP6: Variant 15-99974409-T-C is Benign according to our data. Variant chr15-99974409-T-C is described in ClinVar as Benign. ClinVar VariationId is 315248.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.802 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_139057.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAMTS17	NM_139057.4	MANE Select	c.3281A>G	p.Asn1094Ser	missense	Exon 22 of 22	NP_620688.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAMTS17	ENST00000268070.9	TSL:1 MANE Select	c.3281A>G	p.Asn1094Ser	missense	Exon 22 of 22	ENSP00000268070.4
	ADAMTS17	ENST00000961098.1		c.3431A>G	p.Asn1144Ser	missense	Exon 24 of 24	ENSP00000631157.1
	ADAMTS17	ENST00000568565.2	TSL:5	c.3362A>G	p.Asn1121Ser	missense	Exon 23 of 23	ENSP00000456161.2

Frequencies

GnomAD3 genomes AF: 0.699 AC: 106268 AN: 151998 Hom.: 37633 Cov.: 33

Gnomad AFR AF: 0.809

Gnomad AMI AF: 0.688

Gnomad AMR AF: 0.609

Gnomad ASJ AF: 0.644

Gnomad EAS AF: 0.557

Gnomad SAS AF: 0.669

Gnomad FIN AF: 0.749

Gnomad MID AF: 0.564

Gnomad NFE AF: 0.662

Gnomad OTH AF: 0.650

GnomAD2 exomes AF: 0.657 AC: 165241 AN: 251370 AF XY: 0.658

Gnomad AFR exome AF: 0.815

Gnomad AMR exome AF: 0.548

Gnomad ASJ exome AF: 0.637

Gnomad EAS exome AF: 0.564

Gnomad FIN exome AF: 0.750

Gnomad NFE exome AF: 0.665

Gnomad OTH exome AF: 0.648

GnomAD4 exome AF: 0.664 AC: 970881 AN: 1461762 Hom.: 324357 Cov.: 75 AF XY: 0.664 AC XY: 482838 AN XY: 727172

African (AFR) AF: 0.814 AC: 27258 AN: 33480

American (AMR) AF: 0.558 AC: 24962 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.643 AC: 16792 AN: 26134

East Asian (EAS) AF: 0.515 AC: 20425 AN: 39698

South Asian (SAS) AF: 0.663 AC: 57227 AN: 86258

European-Finnish (FIN) AF: 0.756 AC: 40301 AN: 53338

Middle Eastern (MID) AF: 0.585 AC: 3372 AN: 5764

European-Non Finnish (NFE) AF: 0.666 AC: 740789 AN: 1111982

Other (OTH) AF: 0.658 AC: 39755 AN: 60386

GnomAD4 genome AF: 0.699 AC: 106361 AN: 152116 Hom.: 37672 Cov.: 33 AF XY: 0.699 AC XY: 51993 AN XY: 74372

African (AFR) AF: 0.809 AC: 33602 AN: 41512

American (AMR) AF: 0.608 AC: 9299 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.644 AC: 2235 AN: 3470

East Asian (EAS) AF: 0.557 AC: 2868 AN: 5146

South Asian (SAS) AF: 0.669 AC: 3223 AN: 4820

European-Finnish (FIN) AF: 0.749 AC: 7941 AN: 10600

Middle Eastern (MID) AF: 0.568 AC: 166 AN: 292

European-Non Finnish (NFE) AF: 0.663 AC: 45035 AN: 67972

Other (OTH) AF: 0.648 AC: 1365 AN: 2108

Alfa AF: 0.669 Hom.: 141252

Bravo AF: 0.691

TwinsUK AF: 0.664 AC: 2462

ALSPAC AF: 0.664 AC: 2559

ESP6500AA AF: 0.810 AC: 3570

ESP6500EA AF: 0.665 AC: 5722

ExAC AF: 0.661 AC: 80304

Asia WGS AF: 0.628 AC: 2186 AN: 3478

EpiCase AF: 0.649

EpiControl AF: 0.643

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	Weill-Marchesani 4 syndrome, recessive (3)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.055
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	14
DANN	Benign	0.53
DEOGEN2	Benign	0.012	T
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.52
FATHMM_MKL	Benign	0.032	N
LIST_S2	Benign	0.35	T
MetaRNN	Benign	8.2e-7	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		2.6
PrimateAI	Benign	0.36	T
PROVEAN	Benign	0.13	N
REVEL	Benign	0.089
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.089
MPC		0.074
ClinPred		0.0021	T
GERP RS		4.1
Varity_R		0.030
gMVP		0.31
Mutation Taster		=99/1	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: rs2573652; hg19: chr15-100514614; COSMIC: COSV51490263; COSMIC: COSV51490263;