dbSNP rs781608340: PPEF1:p.Arg463Gly (chrX-18806538-C-G) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001377996.1(PPEF1):c.1387C>G(p.Arg463Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000457 in 1,094,296 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R463H) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 0.0000046 ( 0 hom. 2 hem. )

Consequence

PPEF1
NM_001377996.1 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.773

Publications

1 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: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.06242305).

BS2

High Hemizygotes in GnomAdExome4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPEF1	NM_001377996.1 link	c.1387C>G	p.Arg463Gly	missense_variant	Exon 12 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.1387C>G	p.Arg463Gly	missense_variant	Exon 12 of 16	3	NM_001377996.1	ENSP00000419273.2		O14829-1H7C592

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000457

AC:

AN:

1094296

Hom.:

Cov.:

AF XY:

0.00000556

AC XY:

AN XY:

359902

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26333

American (AMR)

AF:

0.00

AC:

AN:

34927

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19169

East Asian (EAS)

AF:

0.0000331

AC:

AN:

30177

South Asian (SAS)

AF:

0.00

AC:

AN:

53320

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40388

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4099

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

839948

Other (OTH)

AF:

0.0000871

AC:

AN:

45935

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.82

CADD

Benign

7.0

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.53

D;.

FATHMM_MKL

Benign

0.27

LIST_S2

Benign

0.62

T;T

M_CAP

Benign

0.014

MetaRNN

Benign

0.062

T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

1.9

L;.

PhyloP100

0.77

PrimateAI

Benign

0.25

PROVEAN

Uncertain

-3.3

D;D

REVEL

Benign

0.032

Sift

Benign

0.038

D;T

Sift4G

Uncertain

0.031

D;D

Polyphen

0.25

B;B

Vest4

0.11

MutPred

0.47

Loss of MoRF binding (P = 0.068);.;

MVP

0.14

MPC

0.70

ClinPred

0.20

GERP RS

-4.2

Varity_R

0.13

gMVP

0.49

Mutation Taster

=94/6

polymorphism

(source)

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

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rs781608340

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over