Variant chr5-33549326-G-A 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_030955.4(ADAMTS12):c.4183C>T(p.Arg1395Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000103 in 1,461,886 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.000010 ( 0 hom. )

Consequence

ADAMTS12
NM_030955.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.767

Variant links:

Genes affected

ADAMTS12 (HGNC:14605): (ADAM metallopeptidase with thrombospondin type 1 motif 12) 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-1) motif. Individual members of this family differ in the number of C-terminal TS-1 motifs, and some have unique C-terminal domains. The enzyme encoded by this gene contains eight TS-1 motifs. It may play roles in pulmonary cells during fetal development or in tumor processes through its proteolytic activity or as a molecule potentially involved in regulation of cell adhesion. [provided by RefSeq, Jul 2008]

ADAMTS12 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=0.17529127).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADAMTS12	NM_030955.4 linkuse as main transcript	c.4183C>T	p.Arg1395Trp	missense_variant	21/24	ENST00000504830.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADAMTS12	ENST00000504830.6 linkuse as main transcript	c.4183C>T	p.Arg1395Trp	missense_variant	21/24	1	NM_030955.4	P1	P58397-1
ADAMTS12	ENST00000352040.7 linkuse as main transcript	c.3928C>T	p.Arg1310Trp	missense_variant	19/22	1			P58397-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251404

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135878

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:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000103

AC:

AN:

1461886

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727246

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:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000126

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 14, 2023

The c.4183C>T (p.R1395W) alteration is located in exon 21 (coding exon 21) of the ADAMTS12 gene. This alteration results from a C to T substitution at nucleotide position 4183, causing the arginine (R) at amino acid position 1395 to be replaced by a tryptophan (W). 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

0.075

BayesDel_addAF

Benign

-0.095

BayesDel_noAF

Benign

-0.37

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.37

T;.

Eigen

Benign

-0.31

Eigen_PC

Benign

-0.27

FATHMM_MKL

Benign

0.44

LIST_S2

Benign

0.82

T;T

M_CAP

Benign

0.021

MetaRNN

Benign

0.18

T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

2.0

M;.

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.22

PROVEAN

Pathogenic

-4.8

D;D

REVEL

Benign

0.21

Sift

Benign

0.042

D;D

Sift4G

Uncertain

0.033

D;D

Polyphen

0.0090

B;B

Vest4

0.25

MutPred

0.53

Loss of disorder (P = 0.0078);.;

MVP

0.66

MPC

0.16

ClinPred

0.96

GERP RS

1.1

Varity_R

0.085

gMVP

0.38

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