Variant 12-81294958-T-G details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_003625.5(PPFIA2):c.2802A>C(p.Leu934Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,416 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

PPFIA2
NM_003625.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.414

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:

PPFIA2-AS1 (HGNC:53397): (PPFIA2 antisense RNA 1)

PPFIA2-AS1 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/exons	MANE	UniProt
PPFIA2	NM_003625.5 linkuse as main transcript	c.2802A>C	p.Leu934Phe	missense_variant	24/33	ENST00000549396.6
PPFIA2-AS1	NR_120491.1 linkuse as main transcript	n.357-1676T>G		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.2802A>C	p.Leu934Phe	missense_variant	24/33	1	NM_003625.5	A1	O75334-1
PPFIA2-AS1	ENST00000549161.5 linkuse as main transcript	n.579-1676T>G		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000402

AC:

AN:

248542

Hom.:

AF XY:

0.00000742

AC XY:

AN XY:

134856

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:

0.00000888

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461416

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726964

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:

8.99e-7

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

Jun 03, 2024

The c.2802A>C (p.L934F) alteration is located in exon 24 (coding exon 22) of the PPFIA2 gene. This alteration results from a A to C substitution at nucleotide position 2802, causing the leucine (L) at amino acid position 934 to be replaced by a phenylalanine (F). 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

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Uncertain

0.070

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.59

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

Eigen

Benign

-0.30

Eigen_PC

Benign

-0.35

FATHMM_MKL

Benign

0.32

LIST_S2

Pathogenic

1.0

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

M_CAP

Benign

0.051

MetaRNN

Uncertain

0.55

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

MetaSVM

Benign

-0.75

MutationAssessor

Pathogenic

3.0

.;.;M;.;.;.;.;.;M;.;M

MutationTaster

Benign

1.0

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

PrimateAI

Pathogenic

0.86

PROVEAN

Uncertain

-4.0

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

REVEL

Uncertain

0.42

Sift

Uncertain

0.0010

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

Sift4G

Uncertain

0.032

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

Polyphen

1.0

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

Vest4

0.65

MutPred

0.66

.;.;Loss of helix (P = 0.1299);Loss of helix (P = 0.1299);.;.;.;.;Loss of helix (P = 0.1299);.;Loss of helix (P = 0.1299);

MVP

0.85

MPC

2.5

ClinPred

0.99

GERP RS

0.36

Varity_R

0.87

gMVP

0.89

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