X-18779026-A-T

Variant names:

• chrX-18779026-A-T
• NM_001377996.1:c.575A>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001377996.1(PPEF1):​c.575A>T​(p.Glu192Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E192G) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 22)
• Consequence: PPEF1 NM_001377996.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0260
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08891079).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPEF1	NM_001377996.1	c.575A>T	p.Glu192Val	missense_variant	Exon 7 of 16	ENST00000470157.2	NP_001364925.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PPEF1	ENST00000470157.2	c.575A>T	p.Glu192Val	missense_variant	Exon 7 of 16	3	NM_001377996.1	ENSP00000419273.2

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 22

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 24, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.575A>T (p.E192V) alteration is located in exon 10 (coding exon 7) of the PPEF1 gene. This alteration results from a A to T substitution at nucleotide position 575, causing the glutamic acid (E) at amino acid position 192 to be replaced by a valine (V). 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	0.14
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	0.10
DANN	Benign	0.39
DEOGEN2	Uncertain	0.49	T;.;.
FATHMM_MKL	Benign	0.055	N
LIST_S2	Benign	0.40	T;T;T
M_CAP	Benign	0.055	D
MetaRNN	Benign	0.089	T;T;T
MetaSVM	Benign	-0.76	T
MutationAssessor	Uncertain	2.2	M;M;.
PhyloP100		0.026
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-2.0	N;N;N
REVEL	Benign	0.18
Sift	Benign	0.38	T;T;T
Sift4G	Benign	0.35	T;T;T
Polyphen		0.0050	B;B;.
Vest4		0.20
MutPred		0.38		Loss of disorder (P = 0.0206);Loss of disorder (P = 0.0206);.;
MVP		0.48
MPC		0.60
ClinPred		0.23	T
GERP RS		-2.5
Varity_R		0.14
gMVP		0.73
Mutation Taster		=94/6	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

hg19: chrX-18797144;