X-18824033-G-A

Position:

• chrX-18824033-G-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001377996.1(PPEF1):​c.1612G>A​(p.Val538Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000128 in 1,092,336 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 6 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.000013 (0 hom. 6 hem.)
• Consequence: PPEF1 NM_001377996.1 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.397

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]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.069727).
• BS2: High Hemizygotes in GnomAdExome4 at 6 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PPEF1	NM_001377996.1	c.1612G>A	p.Val538Ile	missense_variant	14/16	ENST00000470157.2	NP_001364925.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PPEF1	ENST00000470157.2	c.1612G>A	p.Val538Ile	missense_variant	14/16	3	NM_001377996.1	ENSP00000419273.2

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.0000128 AC: 14 AN: 1092336 Hom.: 0 Cov.: 30 AF XY: 0.0000168 AC XY: 6 AN XY: 358038

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: 0.0000187

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000155

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 14, 2024

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.99
CADD	Benign	0.013
DANN	Benign	0.75
DEOGEN2	Benign	0.077	T;.
FATHMM_MKL	Benign	0.047	N
LIST_S2	Benign	0.57	T;T
M_CAP	Benign	0.0092	T
MetaRNN	Benign	0.070	T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.51	N;.
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.27	N;N
REVEL	Benign	0.084
Sift	Benign	0.33	T;T
Sift4G	Benign	0.24	T;T
Polyphen		0.095	B;B
Vest4		0.038
MutPred		0.52		Loss of phosphorylation at Y540 (P = 0.1268);.;
MVP		0.20
MPC		0.41
ClinPred		0.075	T
GERP RS		-2.4
Varity_R		0.041
gMVP		0.42

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

Other links and lift over

dbSNP: rs779955492; hg19: chrX-18842151; COSMIC: COSV62995524;