rs17070967

Variant names:

• chr3-64541599-T-C
• rs17070967
• NM_182920.2:c.5219A>G

Your query was ambiguous. Multiple possible variants found:

• chr3-64541599-T-C
• chr3-64541599-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_182920.2(ADAMTS9):​c.5219A>G​(p.Lys1740Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00802 in 1,614,014 control chromosomes in the GnomAD database, including 502 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 (★★).

• Frequency:
  • Genomes: 𝑓 0.0099 (51 hom., cov: 32)
  • Exomes 𝑓: 0.0078 (451 hom.)
• Consequence: ADAMTS9 NM_182920.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.18
• Publications: 12 publications found

Genes affected

ADAMTS9 (HGNC:13202): (ADAM metallopeptidase with thrombospondin type 1 motif 9) This gene encodes a member of the ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) protein family. Members of the family 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. Members of the ADAMTS family have been implicated in the cleavage of proteoglycans, the control of organ shape during development, and the inhibition of angiogenesis. This gene is localized to chromosome 3p14.3-p14.2, an area known to be lost in hereditary renal tumors. Alternative splicing results in multiple transcript variants encoding different isoforms that may undergo similar proteolytic processing. [provided by RefSeq, Jan 2016]

ADAMTS9 Gene-Disease associations (from GenCC):

• nephronophthisis 1

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• ciliopathy

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.0030217767).
• BP6: Variant 3-64541599-T-C is Benign according to our data. Variant chr3-64541599-T-C is described in ClinVar as Benign. ClinVar VariationId is 1251224.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.071 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_182920.2. 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
	ADAMTS9	NM_182920.2	MANE Select	c.5219A>G	p.Lys1740Arg	missense	Exon 34 of 40	NP_891550.1
	ADAMTS9	NM_001318781.2		c.5135A>G	p.Lys1712Arg	missense	Exon 33 of 39	NP_001305710.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAMTS9	ENST00000498707.5	TSL:1 MANE Select	c.5219A>G	p.Lys1740Arg	missense	Exon 34 of 40	ENSP00000418735.1
	ADAMTS9	ENST00000295903.8	TSL:1	c.5135A>G	p.Lys1712Arg	missense	Exon 33 of 39	ENSP00000295903.4
	ADAMTS9	ENST00000481060.2	TSL:2	c.2384A>G	p.Lys795Arg	missense	Exon 15 of 21	ENSP00000417521.1

Frequencies

GnomAD3 genomes AF: 0.00983 AC: 1496 AN: 152136 Hom.: 47 Cov.: 32

Gnomad AFR AF: 0.00249

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0446

Gnomad ASJ AF: 0.00375

Gnomad EAS AF: 0.0769

Gnomad SAS AF: 0.0356

Gnomad FIN AF: 0.00499

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000676

Gnomad OTH AF: 0.0138

GnomAD2 exomes AF: 0.0233 AC: 5855 AN: 250830 AF XY: 0.0209

Gnomad AFR exome AF: 0.00174

Gnomad AMR exome AF: 0.0941

Gnomad ASJ exome AF: 0.00278

Gnomad EAS exome AF: 0.0763

Gnomad FIN exome AF: 0.00351

Gnomad NFE exome AF: 0.000926

Gnomad OTH exome AF: 0.0147

GnomAD4 exome AF: 0.00782 AC: 11433 AN: 1461760 Hom.: 451 Cov.: 35 AF XY: 0.00810 AC XY: 5888 AN XY: 727194

African (AFR) AF: 0.00140 AC: 47 AN: 33478

American (AMR) AF: 0.0914 AC: 4087 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00272 AC: 71 AN: 26132

East Asian (EAS) AF: 0.0835 AC: 3314 AN: 39698

South Asian (SAS) AF: 0.0295 AC: 2541 AN: 86254

European-Finnish (FIN) AF: 0.00313 AC: 167 AN: 53396

Middle Eastern (MID) AF: 0.00260 AC: 15 AN: 5768

European-Non Finnish (NFE) AF: 0.000593 AC: 659 AN: 1111922

Other (OTH) AF: 0.00881 AC: 532 AN: 60392

GnomAD4 genome AF: 0.00991 AC: 1509 AN: 152254 Hom.: 51 Cov.: 32 AF XY: 0.0117 AC XY: 870 AN XY: 74450

African (AFR) AF: 0.00248 AC: 103 AN: 41534

American (AMR) AF: 0.0452 AC: 692 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00375 AC: 13 AN: 3466

East Asian (EAS) AF: 0.0773 AC: 400 AN: 5176

South Asian (SAS) AF: 0.0361 AC: 174 AN: 4824

European-Finnish (FIN) AF: 0.00499 AC: 53 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000676 AC: 46 AN: 68020

Other (OTH) AF: 0.0132 AC: 28 AN: 2116

Alfa AF: 0.00710 Hom.: 108

Bravo AF: 0.0141

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.00227 AC: 10

ESP6500EA AF: 0.000814 AC: 7

ExAC AF: 0.0204 AC: 2476

Asia WGS AF: 0.0510 AC: 177 AN: 3478

EpiCase AF: 0.000709

EpiControl AF: 0.000948

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	ADAMTS9-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	14
DANN	Uncertain	0.98
DEOGEN2	Benign	0.063	T
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.14
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.67	T
MetaRNN	Benign	0.0030	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.2	L
PhyloP100		1.2
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.024
Sift	Benign	0.24	T
Sift4G	Benign	0.32	T
Polyphen		0.0060	B
Vest4		0.068
MPC		0.16
ClinPred		0.0031	T
GERP RS		3.4
Varity_R		0.057
gMVP		0.29
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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: rs17070967; hg19: chr3-64527275; COSMIC: COSV55777356; COSMIC: COSV55777356;