Variant 4-72283678-T-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_014243.3(ADAMTS3):c.3076A>C(p.Ile1026Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000139 in 1,442,998 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

ADAMTS3
NM_014243.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.02

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 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
ADAMTS3	NM_014243.3 linkuse as main transcript	c.3076A>C	p.Ile1026Leu	missense_variant	22/22	ENST00000286657.10
ADAMTS3	XM_011532421.2 linkuse as main transcript	c.3019A>C	p.Ile1007Leu	missense_variant	22/22
ADAMTS3	XM_011532422.4 linkuse as main transcript	c.2992A>C	p.Ile998Leu	missense_variant	22/22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADAMTS3	ENST00000286657.10 linkuse as main transcript	c.3076A>C	p.Ile1026Leu	missense_variant	22/22	1	NM_014243.3	P1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000123

AC:

AN:

243190

Hom.:

AF XY:

0.00

AC XY:

AN XY:

131232

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000165

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000139

AC:

AN:

1442998

Hom.:

Cov.:

AF XY:

0.00000140

AC XY:

AN XY:

714572

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000510

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000165

AC:

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

Oct 02, 2023

The c.3076A>C (p.I1026L) alteration is located in exon 22 (coding exon 22) of the ADAMTS3 gene. This alteration results from a A to C substitution at nucleotide position 3076, causing the isoleucine (I) at amino acid position 1026 to be replaced by a leucine (L). 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

Uncertain

0.35

BayesDel_addAF

Benign

-0.062

BayesDel_noAF

Uncertain

-0.060

CADD

Uncertain

DANN

Uncertain

0.98

DEOGEN2

Benign

0.017

T;T

Eigen

Uncertain

0.61

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Uncertain

0.94

M_CAP

Benign

0.016

MetaRNN

Uncertain

0.56

D;D

MetaSVM

Benign

-0.61

MutationAssessor

Uncertain

2.6

M;M

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.80

PROVEAN

Benign

-0.94

N;.

REVEL

Benign

0.15

Sift

Benign

0.12

T;.

Sift4G

Benign

0.17

T;T

Polyphen

0.95

P;P

Vest4

0.62

MutPred

0.67

Gain of disorder (P = 0.0652);Gain of disorder (P = 0.0652);

MVP

0.76

MPC

0.15

ClinPred

0.41

GERP RS

5.3

Varity_R

0.27

gMVP

0.40

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