rs17070905

chr3-64522181-C-T

Variant summary

Our verdict is Benign. Variant got -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. 14/20 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 Likely benignin UniProt.

• 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:3
• Conservation: PhyloP100: 0.558

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]

ACMG classification

Verdict is Benign. Variant got -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADAMTS9	NM_182920.2	c.5798G>A	p.Arg1933Gln	missense_variant	39/40	ENST00000498707.5
ADAMTS9	NM_001318781.2	c.5714G>A	p.Arg1905Gln	missense_variant	38/39
ADAMTS9	XR_007095711.1	n.6057G>A		non_coding_transcript_exon_variant	38/40
ADAMTS9	XR_245151.1	n.6141G>A		non_coding_transcript_exon_variant	39/41

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADAMTS9	ENST00000498707.5	c.5798G>A	p.Arg1933Gln	missense_variant	39/40	1	NM_182920.2	P1

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

GnomAD3 exomes AF: 0.0226 AC: 5667 AN: 251268 Hom.: 258 AF XY: 0.0202 AC XY: 2738 AN XY: 135800

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 SAS exome AF: 0.0281

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

Gnomad4 AFR exome AF: 0.00143

Gnomad4 AMR exome AF: 0.0933

Gnomad4 ASJ exome AF: 0.00279

Gnomad4 EAS exome AF: 0.0750

Gnomad4 SAS exome AF: 0.0291

Gnomad4 FIN exome AF: 0.00350

Gnomad4 NFE exome AF: 0.000681

Gnomad4 OTH exome AF: 0.00864

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

Gnomad4 AFR AF: 0.00250

Gnomad4 AMR AF: 0.0495

Gnomad4 ASJ AF: 0.00374

Gnomad4 EAS AF: 0.0673

Gnomad4 SAS AF: 0.0365

Gnomad4 FIN AF: 0.00555

Gnomad4 NFE AF: 0.000838

Gnomad4 OTH AF: 0.0137

Alfa AF: 0.00631 Hom.: 62

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:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2021	- -

ADAMTS9-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 12, 2019

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 v4.3

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;T
MetaRNN	Benign	0.0020	T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-1.3	N;.
MutationTaster	Benign	0.95	N;N
PrimateAI	Benign	0.26	T
PROVEAN	Benign	1.8	N;N
REVEL	Benign	0.046
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;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

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: rs17070905; hg19: chr3-64507857; COSMIC: COSV55777338;