NM_003625.5:c.3355G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_003625.5(PPFIA2):c.3355G>A(p.Ala1119Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00269 in 1,597,052 control chromosomes in the GnomAD database, including 114 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.015 ( 57 hom., cov: 30)

Exomes 𝑓: 0.0014 ( 57 hom. )

Consequence

PPFIA2
NM_003625.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 3.66

Publications

6 publications found

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 Gene-Disease associations (from GenCC):

neurodevelopmental disorder
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

PPFIA2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.006010115).

BP6

Variant 12-81268043-C-T is Benign according to our data. Variant chr12-81268043-C-T is described in ClinVar as Benign. ClinVar VariationId is 790120.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAdExome4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0502 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003625.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PPFIA2	NM_003625.5	MANE Select	c.3355G>A	p.Ala1119Thr	missense	Exon 29 of 33	NP_003616.2
PPFIA2	NM_001220476.2		c.3337G>A	p.Ala1113Thr	missense	Exon 28 of 32	NP_001207405.1	O75334-3
PPFIA2	NM_001220473.3		c.3355G>A	p.Ala1119Thr	missense	Exon 28 of 31	NP_001207402.1	G3V200

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PPFIA2	ENST00000549396.6	TSL:1 MANE Select	c.3355G>A	p.Ala1119Thr	missense	Exon 29 of 33	ENSP00000450337.1	O75334-1
PPFIA2	ENST00000548586.5	TSL:1	c.3337G>A	p.Ala1113Thr	missense	Exon 28 of 31	ENSP00000449338.1	O75334-3
PPFIA2	ENST00000550584.6	TSL:1	c.3355G>A	p.Ala1119Thr	missense	Exon 28 of 31	ENSP00000449558.2	G3V200

Frequencies

GnomAD3 genomes

AF:

0.0146

AC:

2205

AN:

151392

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0514

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00408

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000416

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000177

Gnomad OTH

AF:

0.00624

GnomAD2 exomes

AF:

0.00343

AC:

784

AN:

228352

AF XY:

0.00262

show subpopulations

Gnomad AFR exome

AF:

0.0507

Gnomad AMR exome

AF:

0.00219

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000884

Gnomad OTH exome

AF:

0.000704

GnomAD4 exome

AF:

0.00144

AC:

2079

AN:

1445566

Hom.:

Cov.:

AF XY:

0.00120

AC XY:

858

AN XY:

717326

show subpopulations

African (AFR)

AF:

0.0522

AC:

1730

AN:

33132

American (AMR)

AF:

0.00251

AC:

107

AN:

42656

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25782

East Asian (EAS)

AF:

0.00

AC:

AN:

39278

South Asian (SAS)

AF:

0.0000959

AC:

AN:

83412

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52484

Middle Eastern (MID)

AF:

0.000695

AC:

AN:

5752

European-Non Finnish (NFE)

AF:

0.0000245

AC:

AN:

1103218

Other (OTH)

AF:

0.00339

AC:

203

AN:

59852

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

182

273

364

455

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

116

174

232

290

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0146

AC:

2210

AN:

151486

Hom.:

Cov.:

AF XY:

0.0140

AC XY:

1034

AN XY:

73978

show subpopulations

African (AFR)

AF:

0.0514

AC:

2121

AN:

41254

American (AMR)

AF:

0.00407

AC:

AN:

15218

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3464

East Asian (EAS)

AF:

0.00

AC:

AN:

5164

South Asian (SAS)

AF:

0.000416

AC:

AN:

4802

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10326

Middle Eastern (MID)

AF:

0.00

AC:

AN:

284

European-Non Finnish (NFE)

AF:

0.000177

AC:

AN:

67960

Other (OTH)

AF:

0.00618

AC:

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

190

284

379

474

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00523

Hom.:

Bravo

AF:

0.0168

ESP6500AA

AF:

0.0439

AC:

167

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00429

AC:

518

Asia WGS

AF:

0.00231

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.089

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.17

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.039

Eigen

Benign

0.10

Eigen_PC

Uncertain

0.29

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.90

MetaRNN

Benign

0.0060

MetaSVM

Benign

-0.54

MutationAssessor

Benign

1.7

PhyloP100

3.7

PrimateAI

Uncertain

0.72

PROVEAN

Benign

-1.1

REVEL

Uncertain

0.43

Sift

Uncertain

0.0080

Sift4G

Uncertain

0.021

Polyphen

0.092

Vest4

0.37

MVP

0.61

MPC

1.1

ClinPred

0.034

GERP RS

5.9

Varity_R

0.38

gMVP

0.15

Mutation Taster

=92/8

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over