Variant chr12-81347600-T-C 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_003625.5(PPFIA2):c.2165A>G(p.His722Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000445 in 1,461,592 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000044 ( 0 hom. )

Consequence

PPFIA2
NM_003625.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.48

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:

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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=0.16677618).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PPFIA2	NM_003625.5 linkuse as main transcript	c.2165A>G	p.His722Arg	missense_variant	18/33	ENST00000549396.6
LOC105369872	XR_945148.3 linkuse as main transcript	n.149-2690T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PPFIA2	ENST00000549396.6 linkuse as main transcript	c.2165A>G	p.His722Arg	missense_variant	18/33	1	NM_003625.5	A1	O75334-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000121

AC:

AN:

248928

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

135012

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:

0.0000266

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000445

AC:

AN:

1461592

Hom.:

Cov.:

AF XY:

0.0000454

AC XY:

AN XY:

727086

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:

0.0000522

Gnomad4 OTH exome

AF:

0.000116

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000658

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.000109

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

Mar 08, 2024

The c.2165A>G (p.H722R) alteration is located in exon 18 (coding exon 16) of the PPFIA2 gene. This alteration results from a A to G substitution at nucleotide position 2165, causing the histidine (H) at amino acid position 722 to be replaced by an arginine (R). 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

0.17

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.35

CADD

Pathogenic

DANN

Benign

0.47

DEOGEN2

Benign

0.022

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

Eigen

Benign

0.13

Eigen_PC

Uncertain

0.26

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.81

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

M_CAP

Benign

0.010

MetaRNN

Benign

0.17

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

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.25

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

MutationTaster

Benign

1.0

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

PrimateAI

Pathogenic

0.87

PROVEAN

Benign

-0.23

.;N;N;N;N;D;N;N;N;N

REVEL

Benign

0.20

Sift

Benign

1.0

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

Sift4G

Benign

1.0

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

Polyphen

0.93

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

Vest4

0.30

MVP

0.56

MPC

0.41

ClinPred

0.27

GERP RS

5.5

Varity_R

0.26

gMVP

0.37

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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