chr3-64522181-C-T

Variant names:

• chr3-64522181-C-T
• rs17070905
• NM_182920.2:c.5798G>A

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.5798G>A​(p.Arg1933Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00793 in 1,613,902 control chromosomes in the GnomAD database, including 485 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.010 (56 hom., cov: 33)
  • Exomes 𝑓: 0.0077 (429 hom.)
• Consequence: ADAMTS9 NM_182920.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.558
• Publications: 13 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=0.0020031333).
• BP6: Variant 3-64522181-C-T is Benign according to our data. Variant chr3-64522181-C-T is described in ClinVar as Benign. ClinVar VariationId is 1294798.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0615 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.5798G>A	p.Arg1933Gln	missense	Exon 39 of 40	NP_891550.1
	ADAMTS9	NM_001318781.2		c.5714G>A	p.Arg1905Gln	missense	Exon 38 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.5798G>A	p.Arg1933Gln	missense	Exon 39 of 40	ENSP00000418735.1
	ADAMTS9	ENST00000295903.8	TSL:1	c.5714G>A	p.Arg1905Gln	missense	Exon 38 of 39	ENSP00000295903.4
	ADAMTS9	ENST00000481060.2	TSL:2	c.2963G>A	p.Arg988Gln	missense	Exon 20 of 21	ENSP00000417521.1

Frequencies

GnomAD3 genomes AF: 0.0101 AC: 1530 AN: 152210 Hom.: 53 Cov.: 33

Gnomad AFR AF: 0.00251

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0488

Gnomad ASJ AF: 0.00374

Gnomad EAS AF: 0.0670

Gnomad SAS AF: 0.0360

Gnomad FIN AF: 0.00555

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000838

Gnomad OTH AF: 0.0143

GnomAD2 exomes AF: 0.0226 AC: 5667 AN: 251268 AF XY: 0.0202

Gnomad AFR exome AF: 0.00178

Gnomad AMR exome AF: 0.0964

Gnomad ASJ exome AF: 0.00288

Gnomad EAS exome AF: 0.0614

Gnomad FIN exome AF: 0.00397

Gnomad NFE exome AF: 0.00109

Gnomad OTH exome AF: 0.0137

GnomAD4 exome AF: 0.00770 AC: 11258 AN: 1461574 Hom.: 429 Cov.: 30 AF XY: 0.00799 AC XY: 5809 AN XY: 727102

African (AFR) AF: 0.00143 AC: 48 AN: 33454

American (AMR) AF: 0.0933 AC: 4167 AN: 44682

Ashkenazi Jewish (ASJ) AF: 0.00279 AC: 73 AN: 26128

East Asian (EAS) AF: 0.0750 AC: 2978 AN: 39688

South Asian (SAS) AF: 0.0291 AC: 2510 AN: 86246

European-Finnish (FIN) AF: 0.00350 AC: 187 AN: 53408

Middle Eastern (MID) AF: 0.00278 AC: 16 AN: 5764

European-Non Finnish (NFE) AF: 0.000681 AC: 757 AN: 1111820

Other (OTH) AF: 0.00864 AC: 522 AN: 60384

GnomAD4 genome AF: 0.0101 AC: 1543 AN: 152328 Hom.: 56 Cov.: 33 AF XY: 0.0120 AC XY: 892 AN XY: 74508

African (AFR) AF: 0.00250 AC: 104 AN: 41582

American (AMR) AF: 0.0495 AC: 757 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00374 AC: 13 AN: 3472

East Asian (EAS) AF: 0.0673 AC: 348 AN: 5170

South Asian (SAS) AF: 0.0365 AC: 176 AN: 4828

European-Finnish (FIN) AF: 0.00555 AC: 59 AN: 10622

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

European-Non Finnish (NFE) AF: 0.000838 AC: 57 AN: 68024

Other (OTH) AF: 0.0137 AC: 29 AN: 2116

Alfa AF: 0.00719 Hom.: 105

Bravo AF: 0.0142

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.00227 AC: 10

ESP6500EA AF: 0.000930 AC: 8

ExAC AF: 0.0194 AC: 2360

Asia WGS AF: 0.0510 AC: 176 AN: 3478

EpiCase AF: 0.000818

EpiControl AF: 0.00113

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

May 04, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ADAMTS9-related disorder Benign:1

Jun 12, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	15
DANN	Benign	0.44
DEOGEN2	Benign	0.037	T
Eigen	Benign	-0.80
Eigen_PC	Benign	-0.58
FATHMM_MKL	Benign	0.48	N
LIST_S2	Benign	0.81	T
MetaRNN	Benign	0.0020	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-1.3	N
PhyloP100		0.56
PrimateAI	Benign	0.26	T
PROVEAN	Benign	1.8	N
REVEL	Benign	0.046
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.042
MPC		0.22
ClinPred		0.014	T
GERP RS		0.86
Varity_R		0.054
gMVP		0.17
Mutation Taster		=98/2	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: rs17070905; hg19: chr3-64507857; COSMIC: COSV55777338;