Genetic Variant PPEF1:p.Arg592His (chrX-18827300-G-A) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_001377996.1(PPEF1):c.1775G>A(p.Arg592His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000137 in 1,094,697 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 5 hemizygotes in GnomAD. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 0.000014 ( 0 hom. 5 hem. )

Consequence

PPEF1
NM_001377996.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.67

Publications

0 publications found

Variant links:

Genes affected

PPEF1 (HGNC:9243): (protein phosphatase with EF-hand domain 1) This gene encodes a member of the serine/threonine protein phosphatase with EF-hand motif family. The protein contains a protein phosphatase catalytic domain, and at least two EF-hand calcium-binding motifs in its C terminus. Although its substrate(s) is unknown, the encoded protein has been suggested to play a role in specific sensory neuron function and/or development. This gene shares high sequence similarity with the Drosophila retinal degeneration C (rdgC) gene. Several alternatively spliced transcript variants, each encoding a distinct isoform, have been described. [provided by RefSeq, Jul 2008]

PPEF1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BS2

High Hemizygotes in GnomAdExome4 at 5 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPEF1	NM_001377996.1 link	c.1775G>A	p.Arg592His	missense_variant	Exon 16 of 16	ENST00000470157.2	NP_001364925.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PPEF1	ENST00000470157.2 link	c.1775G>A	p.Arg592His	missense_variant	Exon 16 of 16	3	NM_001377996.1	ENSP00000419273.2		O14829-1H7C592

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000164

AC:

AN:

183298

AF XY:

0.0000443

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000144

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000122

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000137

AC:

AN:

1094697

Hom.:

Cov.:

AF XY:

0.0000139

AC XY:

AN XY:

360439

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26339

American (AMR)

AF:

0.00

AC:

AN:

35194

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19364

East Asian (EAS)

AF:

0.0000663

AC:

AN:

30179

South Asian (SAS)

AF:

0.00

AC:

AN:

54001

European-Finnish (FIN)

AF:

0.0000247

AC:

AN:

40515

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3856

European-Non Finnish (NFE)

AF:

0.0000131

AC:

AN:

839277

Other (OTH)

AF:

0.0000218

AC:

AN:

45972

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.455

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

EpiCase

AF:

0.0000546

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

Feb 25, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1775G>A (p.R592H) alteration is located in exon 19 (coding exon 16) of the PPEF1 gene. This alteration results from a G to A substitution at nucleotide position 1775, causing the arginine (R) at amino acid position 592 to be replaced by a histidine (H). 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

0.068

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.50

CADD

Benign

(source)

DANN

Uncertain

0.97

DEOGEN2

Benign

0.33

T;.;T

FATHMM_MKL

Uncertain

0.84

LIST_S2

Benign

0.84

T;T;T

M_CAP

Uncertain

0.11

MetaRNN

Uncertain

0.43

T;T;T

MetaSVM

Benign

-0.71

MutationAssessor

Benign

1.7

L;.;.

PhyloP100

2.7

PrimateAI

Benign

0.22

PROVEAN

Uncertain

-2.8

D;N;D

REVEL

Benign

0.17

Sift

Benign

0.11

T;T;T

Sift4G

Benign

0.18

T;T;T

Polyphen

0.74

P;B;.

Vest4

0.071

MutPred

0.66

Gain of ubiquitination at K596 (P = 0.0513);.;.;

MVP

0.76

MPC

0.84

ClinPred

0.074

GERP RS

2.4

Varity_R

0.077

gMVP

0.79

Mutation Taster

=90/10

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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X-18827300-G-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over