12-81347548-C-T

Variant names:

Variant summary

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

The NM_003625.5(PPFIA2):c.2217G>A(p.Met739Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000187 in 1,607,326 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 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

PPFIA2
NM_003625.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.06

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:

LOC105369872 (HGNC:):

LOC105369872 links:

Genome browser will be placed here

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=0.28408068).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPFIA2	NM_003625.5 link	c.2217G>A	p.Met739Ile	missense_variant	Exon 18 of 33	ENST00000549396.6	NP_003616.2	O75334-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PPFIA2	ENST00000549396.6 link	c.2217G>A	p.Met739Ile	missense_variant	Exon 18 of 33	1	NM_003625.5	ENSP00000450337.1		O75334-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152158

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000402

AC:

AN:

248898

Hom.:

AF XY:

0.00000741

AC XY:

AN XY:

135006

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:

0.00000887

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.87e-7

AC:

AN:

1455168

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

724364

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:

9.04e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152158

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74334

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:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.00000378

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000120

AC:

ExAC

AF:

0.00000827

AC:

EpiCase

AF:

0.0000545

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

Jan 10, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2217G>A (p.M739I) alteration is located in exon 18 (coding exon 16) of the PPFIA2 gene. This alteration results from a G to A substitution at nucleotide position 2217, causing the methionine (M) at amino acid position 739 to be replaced by an isoleucine (I). 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

0.54

BayesDel_addAF

Benign

-0.053

BayesDel_noAF

Benign

-0.31

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Benign

0.047

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

Eigen

Uncertain

0.37

Eigen_PC

Uncertain

0.46

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.81

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

M_CAP

Benign

0.012

MetaRNN

Benign

0.28

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

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.86

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

PrimateAI

Pathogenic

0.89

PROVEAN

Benign

-1.8

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

REVEL

Benign

0.11

Sift

Benign

0.059

.;T;T;T;D;.;D;T;T;T

Sift4G

Benign

0.21

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

Polyphen

0.53

.;P;.;.;.;.;.;.;.;.

Vest4

0.65

MutPred

0.34

.;Loss of methylation at R738 (P = 0.0527);Loss of methylation at R738 (P = 0.0527);.;.;.;.;Loss of methylation at R738 (P = 0.0527);.;Loss of methylation at R738 (P = 0.0527);

MVP

0.19

MPC

0.38

ClinPred

0.52

GERP RS

5.5

Varity_R

0.40

gMVP

0.53

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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