Variant 12-81341204-G-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_003625.5(PPFIA2):c.2267C>A(p.Ala756Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000311 in 1,610,248 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

PPFIA2
NM_003625.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.35

Variant links:

Genes affected

PPFIA2 (HGNC:9246): (PTPRF interacting protein alpha 2) The protein encoded by this gene is a member of the LAR protein-tyrosine phosphatase-interacting protein (liprin) family. Liprins interact with members of LAR family of transmembrane protein tyrosine phosphatases, which are known to be important for axon guidance and mammary gland development. It has been proposed that liprins are multivalent proteins that form complex structures and act as scaffolds for the recruitment and anchoring of LAR family of tyrosine phosphatases. This protein has been shown to bind the calcium/calmodulin-dependent serine protein kinase (MAGUK family) protein (also known as CASK) and proposed to regulate higher-order brain functions in mammals. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2013]

PPFIA2 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.3674752).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PPFIA2	NM_003625.5 linkuse as main transcript	c.2267C>A	p.Ala756Glu	missense_variant	20/33	ENST00000549396.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PPFIA2	ENST00000549396.6 linkuse as main transcript	c.2267C>A	p.Ala756Glu	missense_variant	20/33	1	NM_003625.5	A1	O75334-1

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

151990

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1458258

Hom.:

Cov.:

AF XY:

0.00000276

AC XY:

AN XY:

725434

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:

0.00000360

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000658

AC:

AN:

151990

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74226

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

EpiCase

AF:

0.0000548

EpiControl

AF:

0.00

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

Apr 26, 2023

The c.2267C>A (p.A756E) alteration is located in exon 20 (coding exon 18) of the PPFIA2 gene. This alteration results from a C to A substitution at nucleotide position 2267, causing the alanine (A) at amino acid position 756 to be replaced by a glutamic acid (E). 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

0.47

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Benign

-0.090

CADD

Uncertain

DANN

Benign

0.89

DEOGEN2

Benign

0.041

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

Eigen

Benign

0.026

Eigen_PC

Uncertain

0.25

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.87

D;D;D;D;D;D;D;D;.;D

M_CAP

Benign

0.012

MetaRNN

Benign

0.37

T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.9

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

MutationTaster

Benign

1.0

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

PrimateAI

Pathogenic

0.86

PROVEAN

Benign

-1.4

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

REVEL

Benign

0.22

Sift

Benign

0.44

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

Sift4G

Benign

0.93

T;T;T;T;T;T;T;T;T;T

Polyphen

0.048

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

Vest4

0.64

MutPred

0.26

.;Gain of loop (P = 0.0013);Gain of loop (P = 0.0013);.;.;.;.;Gain of loop (P = 0.0013);.;Gain of loop (P = 0.0013);

MVP

0.43

MPC

0.39

ClinPred

0.62

GERP RS

5.3

Varity_R

0.41

gMVP

0.61

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