Genetic Variant PTP4A2:p.Ala48Val (chr1-31915941-G-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_080391.4(PTP4A2):c.143C>T(p.Ala48Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000342 in 1,606,304 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000040 ( 0 hom., cov: 29)

Exomes 𝑓: 0.000034 ( 0 hom. )

Consequence

PTP4A2
NM_080391.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.84

Variant links:

Genes affected

PTP4A2 (HGNC:9635): (protein tyrosine phosphatase 4A2) The protein encoded by this gene belongs to a small class of the protein tyrosine phosphatase (PTP) family. PTPs are cell signaling molecules that play regulatory roles in a variety of cellular processes. PTPs in this class contain a protein tyrosine phosphatase catalytic domain and a characteristic C-terminal prenylation motif. This PTP has been shown to primarily associate with plasmic and endosomal membrane through its C-terminal prenylation. This PTP was found to interact with the beta-subunit of Rab geranylgeranyltransferase II (beta GGT II), and thus may function as a regulator of GGT II activity. Overexpression of this gene in mammalian cells conferred a transformed phenotype, which suggested its role in tumorigenesis. Alternatively spliced transcript variants have been described. Related pseudogenes exist on chromosomes 11, 12 and 17. [provided by RefSeq, Aug 2010]

PTP4A2 links:

ENSG00000269967 (HGNC:):

ENSG00000269967 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 rank	MANE	Protein	UniProt
PTP4A2	NM_080391.4 link	c.143C>T	p.Ala48Val	missense_variant	Exon 3 of 6	ENST00000647444.2	NP_536316.1	Q12974-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTP4A2	ENST00000647444.2 link	c.143C>T	p.Ala48Val	missense_variant	Exon 3 of 6		NM_080391.4	ENSP00000493688.1		Q12974-1

Frequencies

GnomAD3 genomes

AF:

0.0000397

AC:

AN:

151294

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000883

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000285

AC:

AN:

245902

Hom.:

AF XY:

0.0000451

AC XY:

AN XY:

133176

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:

0.0000627

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000337

AC:

AN:

1455010

Hom.:

Cov.:

AF XY:

0.0000373

AC XY:

AN XY:

723934

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:

0.0000433

Gnomad4 OTH exome

AF:

0.0000167

GnomAD4 genome

AF:

0.0000397

AC:

AN:

151294

Hom.:

Cov.:

AF XY:

0.0000407

AC XY:

AN XY:

73782

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000883

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000772

Hom.:

Bravo

AF:

0.0000567

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 23, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.143C>T (p.A48V) alteration is located in exon 3 (coding exon 2) of the PTP4A2 gene. This alteration results from a C to T substitution at nucleotide position 143, causing the alanine (A) at amino acid position 48 to be replaced by a valine (V). 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

0.23

BayesDel_addAF

Pathogenic

0.20

BayesDel_noAF

Pathogenic

0.24

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.25

T;T;T;.;T;T;T;T

Eigen

Uncertain

0.43

Eigen_PC

Uncertain

0.55

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Benign

0.81

.;.;T;T;T;T;T;T

M_CAP

Benign

0.058

MetaRNN

Uncertain

0.55

D;D;D;D;D;D;D;D

MetaSVM

Uncertain

0.67

MutationAssessor

Benign

1.1

L;L;L;L;.;.;.;.

PrimateAI

Pathogenic

0.80

PROVEAN

Benign

-1.9

.;.;.;.;N;.;.;N

REVEL

Uncertain

0.59

Sift

Benign

0.26

.;.;.;.;T;.;.;T

Sift4G

Benign

0.24

T;.;.;T;T;T;T;T

Polyphen

0.0030

B;B;B;.;.;.;.;.

Vest4

0.47

MVP

0.61

ClinPred

0.30

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.28

gMVP

0.94

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