Variant 4-72283495-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_014243.3(ADAMTS3):c.3259A>G(p.Thr1087Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000233 in 1,461,794 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000023 ( 0 hom. )

Consequence

ADAMTS3
NM_014243.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.57

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.0810197).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
ADAMTS3	NM_014243.3 linkuse as main transcript	c.3259A>G	p.Thr1087Ala	missense_variant	22/22	ENST00000286657.10	NP_055058.2
ADAMTS3	XM_011532421.2 linkuse as main transcript	c.3202A>G	p.Thr1068Ala	missense_variant	22/22		XP_011530723.1
ADAMTS3	XM_011532422.4 linkuse as main transcript	c.3175A>G	p.Thr1059Ala	missense_variant	22/22		XP_011530724.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADAMTS3	ENST00000286657.10 linkuse as main transcript	c.3259A>G	p.Thr1087Ala	missense_variant	22/22	1	NM_014243.3	ENSP00000286657	P1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000797

AC:

AN:

251096

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135704

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000233

AC:

AN:

1461794

Hom.:

Cov.:

AF XY:

0.0000206

AC XY:

AN XY:

727206

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000297

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000312

Hom.:

Bravo

AF:

0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 18, 2022

The c.3259A>G (p.T1087A) alteration is located in exon 22 (coding exon 22) of the ADAMTS3 gene. This alteration results from a A to G substitution at nucleotide position 3259, causing the threonine (T) at amino acid position 1087 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.063

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.50

CADD

Benign

DANN

Benign

0.88

DEOGEN2

Benign

0.043

T;T

Eigen

Benign

-0.82

Eigen_PC

Benign

-0.72

FATHMM_MKL

Uncertain

0.77

LIST_S2

Benign

0.52

.;T

M_CAP

Benign

0.0061

MetaRNN

Benign

0.081

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.1

L;L

MutationTaster

Benign

0.99

PrimateAI

Benign

0.25

PROVEAN

Benign

-1.1

N;.

REVEL

Benign

0.025

Sift

Benign

0.12

T;.

Sift4G

Uncertain

0.041

D;D

Polyphen

0.017

B;B

Vest4

0.16

MutPred

0.20

Gain of glycosylation at Y1092 (P = 0.0042);Gain of glycosylation at Y1092 (P = 0.0042);

MVP

0.58

MPC

0.12

ClinPred

0.049

GERP RS

3.1

Varity_R

0.048

gMVP

0.53

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