chr3-64686798-A-T

Position:

chr3-64686798-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_182920.2(ADAMTS9):c.286T>A(p.Ser96Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0505 in 1,613,648 control chromosomes in the GnomAD database, including 4,496 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 the same amino acid substitution has been previously reported as Likely benign in UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S96P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.10 ( 1379 hom., cov: 33)

Exomes 𝑓: 0.045 ( 3117 hom. )

Consequence

ADAMTS9
NM_182920.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 1.17

Variant links:

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 links:

ADAMTS9-AS2 (HGNC:42435): (ADAMTS9 antisense RNA 2)

ADAMTS9-AS2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0011181235).

BP6

Variant 3-64686798-A-T is Benign according to our data. Variant chr3-64686798-A-T is described in ClinVar as [Benign]. Clinvar id is 1277022.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.219 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADAMTS9	NM_182920.2 link	c.286T>A	p.Ser96Thr	missense_variant	2/40	ENST00000498707.5	NP_891550.1	Q9P2N4-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADAMTS9	ENST00000498707.5 link	c.286T>A	p.Ser96Thr	missense_variant	2/40	1	NM_182920.2	ENSP00000418735.1		Q9P2N4-3

Frequencies

GnomAD3 genomes

AF:

0.103

AC:

15663

AN:

151948

Hom.:

1379

Cov.:

show subpopulations

Gnomad AFR

AF:

0.223

Gnomad AMI

AF:

0.0395

Gnomad AMR

AF:

0.153

Gnomad ASJ

AF:

0.122

Gnomad EAS

AF:

0.0803

Gnomad SAS

AF:

0.0667

Gnomad FIN

AF:

0.0696

Gnomad MID

AF:

0.0918

Gnomad NFE

AF:

0.0286

Gnomad OTH

AF:

0.105

GnomAD3 exomes

AF:

0.0816

AC:

20483

AN:

250874

Hom.:

1452

AF XY:

0.0734

AC XY:

9952

AN XY:

135674

show subpopulations

Gnomad AFR exome

AF:

0.225

Gnomad AMR exome

AF:

0.201

Gnomad ASJ exome

AF:

0.118

Gnomad EAS exome

AF:

0.0757

Gnomad SAS exome

AF:

0.0630

Gnomad FIN exome

AF:

0.0655

Gnomad NFE exome

AF:

0.0312

Gnomad OTH exome

AF:

0.0734

GnomAD4 exome

AF:

0.0450

AC:

65784

AN:

1461584

Hom.:

3117

Cov.:

AF XY:

0.0446

AC XY:

32427

AN XY:

727090

show subpopulations

Gnomad4 AFR exome

AF:

0.230

Gnomad4 AMR exome

AF:

0.198

Gnomad4 ASJ exome

AF:

0.117

Gnomad4 EAS exome

AF:

0.0858

Gnomad4 SAS exome

AF:

0.0649

Gnomad4 FIN exome

AF:

0.0594

Gnomad4 NFE exome

AF:

0.0270

Gnomad4 OTH exome

AF:

0.0574

GnomAD4 genome

AF:

0.103

AC:

15688

AN:

152064

Hom.:

1379

Cov.:

AF XY:

0.104

AC XY:

7713

AN XY:

74324

show subpopulations

Gnomad4 AFR

AF:

0.223

Gnomad4 AMR

AF:

0.153

Gnomad4 ASJ

AF:

0.122

Gnomad4 EAS

AF:

0.0805

Gnomad4 SAS

AF:

0.0672

Gnomad4 FIN

AF:

0.0696

Gnomad4 NFE

AF:

0.0286

Gnomad4 OTH

AF:

0.104

Alfa

AF:

0.0468

Hom.:

240

Bravo

AF:

0.118

TwinsUK

AF:

0.0243

AC:

ALSPAC

AF:

0.0301

AC:

116

ESP6500AA

AF:

0.229

AC:

1007

ESP6500EA

AF:

0.0337

AC:

290

ExAC

AF:

0.0784

AC:

9521

Asia WGS

AF:

0.0830

AC:

290

AN:

3478

EpiCase

AF:

0.0363

EpiControl

AF:

0.0441

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

ADAMTS9-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 30, 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

0.076

BayesDel_addAF

Benign

-0.81

BayesDel_noAF

Benign

-0.79

CADD

Benign

DANN

Benign

0.90

DEOGEN2

Benign

0.051

T;.;.

Eigen

Benign

-0.52

Eigen_PC

Benign

-0.39

FATHMM_MKL

Benign

0.65

LIST_S2

Benign

0.49

T;T;T

MetaRNN

Benign

0.0011

T;T;T

MetaSVM

Benign

-0.92

MutationAssessor

Benign

0.71

N;N;.

PrimateAI

Benign

0.46

PROVEAN

Benign

-0.16

N;N;N

REVEL

Benign

0.048

Sift

Benign

0.56

T;T;T

Sift4G

Benign

0.65

T;T;T

Polyphen

0.0020

B;.;.

Vest4

0.073

MPC

0.18

ClinPred

0.0099

GERP RS

0.91

Varity_R

0.070

gMVP

0.35

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over