chr4-72283311-G-A

Position:

chr4-72283311-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_014243.3(ADAMTS3):c.3443C>T(p.Pro1148Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00174 in 1,613,984 control chromosomes in the GnomAD database, including 47 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 (★★).

Frequency

Genomes: 𝑓 0.0093 ( 28 hom., cov: 32)

Exomes 𝑓: 0.00095 ( 19 hom. )

Consequence

ADAMTS3
NM_014243.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 1.22

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.004003465).

BP6

Variant 4-72283311-G-A is Benign according to our data. Variant chr4-72283311-G-A is described in ClinVar as [Benign]. Clinvar id is 787029.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0093 (1415/152200) while in subpopulation AFR AF= 0.0321 (1334/41520). AF 95% confidence interval is 0.0307. There are 28 homozygotes in gnomad4. There are 648 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 28 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
ADAMTS3	NM_014243.3 linkuse as main transcript	c.3443C>T	p.Pro1148Leu	missense_variant	22/22	ENST00000286657.10
ADAMTS3	XM_011532421.2 linkuse as main transcript	c.3386C>T	p.Pro1129Leu	missense_variant	22/22
ADAMTS3	XM_011532422.4 linkuse as main transcript	c.3359C>T	p.Pro1120Leu	missense_variant	22/22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADAMTS3	ENST00000286657.10 linkuse as main transcript	c.3443C>T	p.Pro1148Leu	missense_variant	22/22	1	NM_014243.3	P1

Frequencies

GnomAD3 genomes

AF:

0.00929

AC:

1413

AN:

152082

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0322

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00334

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000208

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000147

Gnomad OTH

AF:

0.00909

GnomAD3 exomes

AF:

0.00225

AC:

565

AN:

250758

Hom.:

AF XY:

0.00168

AC XY:

228

AN XY:

135476

show subpopulations

Gnomad AFR exome

AF:

0.0320

Gnomad AMR exome

AF:

0.000839

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000707

Gnomad OTH exome

AF:

0.00115

GnomAD4 exome

AF:

0.000950

AC:

1388

AN:

1461784

Hom.:

Cov.:

AF XY:

0.000831

AC XY:

604

AN XY:

727196

show subpopulations

Gnomad4 AFR exome

AF:

0.0356

Gnomad4 AMR exome

AF:

0.00123

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000580

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000189

Gnomad4 OTH exome

AF:

0.00187

GnomAD4 genome

AF:

0.00930

AC:

1415

AN:

152200

Hom.:

Cov.:

AF XY:

0.00871

AC XY:

648

AN XY:

74418

show subpopulations

Gnomad4 AFR

AF:

0.0321

Gnomad4 AMR

AF:

0.00334

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000208

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000147

Gnomad4 OTH

AF:

0.00900

Alfa

AF:

0.00141

Hom.:

Bravo

AF:

0.0106

ESP6500AA

AF:

0.0272

AC:

120

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00264

AC:

321

Asia WGS

AF:

0.00173

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

ADAMTS3-related disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 19, 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). -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.087

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.49

CADD

Benign

6.8

DANN

Uncertain

0.98

DEOGEN2

Benign

0.040

T;T

Eigen

Benign

-0.79

Eigen_PC

Benign

-0.84

FATHMM_MKL

Benign

0.14

LIST_S2

Benign

0.50

.;T

MetaRNN

Benign

0.0040

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.7

L;L

MutationTaster

Benign

1.0

PrimateAI

Benign

0.27

PROVEAN

Benign

-1.1

N;.

REVEL

Benign

0.048

Sift

Benign

0.20

T;.

Sift4G

Benign

0.12

T;T

Polyphen

0.0050

B;B

Vest4

0.067

MVP

0.62

MPC

0.12

ClinPred

0.0038

GERP RS

2.5

Varity_R

0.031

gMVP

0.24

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