chr4-72290961-T-C

Position:

chr4-72290961-T-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_014243.3(ADAMTS3):c.2825A>G(p.Asn942Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00333 in 1,613,996 control chromosomes in the GnomAD database, including 17 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.0028 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0034 ( 16 hom. )

Consequence

ADAMTS3
NM_014243.3 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 3.23

Variant links:

Genes affected

ADAMTS3 (HGNC:219): (ADAM metallopeptidase with thrombospondin type 1 motif 3) 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. The encoded preproprotein is proteolytically processed to generate the mature protease. This protease, a member of the procollagen aminopropeptidase subfamily of proteins, may play a role in the processing of type II fibrillar collagen in articular cartilage. [provided by RefSeq, Feb 2016]

ADAMTS3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008250326).

BP6

Variant 4-72290961-T-C is Benign according to our data. Variant chr4-72290961-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 717678.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-72290961-T-C is described in Lovd as [Benign].

BS2

High Homozygotes in GnomAdExome4 at 16 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
ADAMTS3	NM_014243.3 linkuse as main transcript	c.2825A>G	p.Asn942Ser	missense_variant	20/22	ENST00000286657.10
ADAMTS3	XM_011532421.2 linkuse as main transcript	c.2768A>G	p.Asn923Ser	missense_variant	20/22
ADAMTS3	XM_011532422.4 linkuse as main transcript	c.2741A>G	p.Asn914Ser	missense_variant	20/22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADAMTS3	ENST00000286657.10 linkuse as main transcript	c.2825A>G	p.Asn942Ser	missense_variant	20/22	1	NM_014243.3	P1

Frequencies

GnomAD3 genomes

AF:

0.00278

AC:

423

AN:

152112

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000579

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00406

Gnomad ASJ

AF:

0.00260

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00104

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.00463

Gnomad OTH

AF:

0.00192

GnomAD3 exomes

AF:

0.00244

AC:

613

AN:

251000

Hom.:

AF XY:

0.00240

AC XY:

326

AN XY:

135636

show subpopulations

Gnomad AFR exome

AF:

0.000554

Gnomad AMR exome

AF:

0.00289

Gnomad ASJ exome

AF:

0.00248

Gnomad EAS exome

AF:

0.0000546

Gnomad SAS exome

AF:

0.000882

Gnomad FIN exome

AF:

0.000462

Gnomad NFE exome

AF:

0.00366

Gnomad OTH exome

AF:

0.00424

GnomAD4 exome

AF:

0.00338

AC:

4948

AN:

1461766

Hom.:

Cov.:

AF XY:

0.00336

AC XY:

2440

AN XY:

727184

show subpopulations

Gnomad4 AFR exome

AF:

0.000568

Gnomad4 AMR exome

AF:

0.00282

Gnomad4 ASJ exome

AF:

0.00199

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00117

Gnomad4 FIN exome

AF:

0.000300

Gnomad4 NFE exome

AF:

0.00400

Gnomad4 OTH exome

AF:

0.00233

GnomAD4 genome

AF:

0.00277

AC:

422

AN:

152230

Hom.:

Cov.:

AF XY:

0.00293

AC XY:

218

AN XY:

74440

show subpopulations

Gnomad4 AFR

AF:

0.000578

Gnomad4 AMR

AF:

0.00406

Gnomad4 ASJ

AF:

0.00260

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00104

Gnomad4 FIN

AF:

0.0000942

Gnomad4 NFE

AF:

0.00463

Gnomad4 OTH

AF:

0.00190

Alfa

AF:

0.00397

Hom.:

Bravo

AF:

0.00261

TwinsUK

AF:

0.00270

AC:

ALSPAC

AF:

0.00441

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00360

AC:

ExAC

AF:

0.00245

AC:

297

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00513

EpiControl

AF:

0.00450

ClinVar

Significance: Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Dec 31, 2019	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	ADAMTS3: BP4, BS2 -

not specified

Benign:1

Benign, no assertion criteria provided

clinical testing

Clinical Genetics, Academic Medical Center

- -

ADAMTS3-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 19, 2024

This variant is classified as likely 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

0.079

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.59

CADD

Benign

DANN

Benign

0.93

DEOGEN2

Benign

0.055

T;T

Eigen

Benign

-0.45

Eigen_PC

Benign

-0.33

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.90

.;D

M_CAP

Benign

0.024

MetaRNN

Benign

0.0083

T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

0.82

L;L

MutationTaster

Benign

1.0

PrimateAI

Benign

0.48

PROVEAN

Benign

-1.9

N;.

REVEL

Benign

0.13

Sift

Benign

0.12

T;.

Sift4G

Benign

0.063

T;T

Polyphen

0.065

B;B

Vest4

0.34

MVP

0.66

MPC

0.099

ClinPred

0.018

GERP RS

4.2

Varity_R

0.056

gMVP

0.15

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