Variant 5-179153518-G-T details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_014244.5(ADAMTS2):c.1488C>A(p.Phe496Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,458,278 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. F496F) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

ADAMTS2
NM_014244.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.545

Variant links:

Genes affected

ADAMTS2 (HGNC:218): (ADAM metallopeptidase with thrombospondin type 1 motif 2) 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 procollagen N-proteinase. This proteinase excises the N-propeptide of the fibrillar procollagens types I-III and type V. Mutations in this gene cause Ehlers-Danlos syndrome type VIIC, a recessively inherited connective-tissue disorder. Alternative splicing results in multiple transcript variants, at least one of which encodes an isoform that is proteolytically processed. [provided by RefSeq, Feb 2016]

ADAMTS2 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	Protein	UniProt
ADAMTS2	NM_014244.5 linkuse as main transcript	c.1488C>A	p.Phe496Leu	missense_variant	9/22	ENST00000251582.12	NP_055059.2	O95450-1
ADAMTS2	NM_021599.4 linkuse as main transcript	c.1488C>A	p.Phe496Leu	missense_variant	9/11		NP_067610.1	O95450-2
ADAMTS2	XM_047417895.1 linkuse as main transcript	c.993C>A	p.Phe331Leu	missense_variant	8/21		XP_047273851.1
ADAMTS2	XM_047417896.1 linkuse as main transcript	c.606C>A	p.Phe202Leu	missense_variant	7/20		XP_047273852.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
ADAMTS2	ENST00000251582.12 linkuse as main transcript	c.1488C>A	p.Phe496Leu	missense_variant	9/22	1	NM_014244.5	ENSP00000251582.7	O95450-1
ADAMTS2	ENST00000274609.5 linkuse as main transcript	c.1488C>A	p.Phe496Leu	missense_variant	9/11	1		ENSP00000274609.5	O95450-2
ADAMTS2	ENST00000518335.3 linkuse as main transcript	c.1488C>A	p.Phe496Leu	missense_variant	9/21	3		ENSP00000489888.2	A0A1B0GTY3
ADAMTS2	ENST00000698889.1 linkuse as main transcript	n.1488C>A		non_coding_transcript_exon_variant	9/21			ENSP00000514008.1	A0A8V8TMU7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000404

AC:

AN:

247222

Hom.:

AF XY:

0.00

AC XY:

AN XY:

134264

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:

0.00000888

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.86e-7

AC:

AN:

1458278

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

725670

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:

0.0000200

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Uncertain

0.16

BayesDel_noAF

Uncertain

-0.010

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.80

D;.;.

Eigen

Benign

0.021

Eigen_PC

Benign

-0.21

FATHMM_MKL

Benign

0.23

M_CAP

Uncertain

0.14

MetaRNN

Uncertain

0.69

D;D;D

MetaSVM

Uncertain

-0.13

MutationAssessor

Pathogenic

3.8

H;.;H

PrimateAI

Pathogenic

0.90

PROVEAN

Pathogenic

-5.8

D;.;D

REVEL

Uncertain

0.51

Sift

Uncertain

0.0030

D;.;D

Sift4G

Uncertain

0.050

T;.;D

Polyphen

1.0

D;.;D

Vest4

0.90

MutPred

0.72

Loss of catalytic residue at F496 (P = 0.0221);Loss of catalytic residue at F496 (P = 0.0221);Loss of catalytic residue at F496 (P = 0.0221);

MVP

0.76

MPC

1.3

ClinPred

1.0

GERP RS

-1.8

Varity_R

0.70

gMVP

0.90

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over