X-18733795-T-A

Variant names:

• chrX-18733795-T-A
• NM_001377996.1:c.222T>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001377996.1(PPEF1):​c.222T>A​(p.His74Gln) 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. 15/21 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. H74R) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 23)
• Consequence: PPEF1 NM_001377996.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.45
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06596118).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPEF1	NM_001377996.1	c.222T>A	p.His74Gln	missense_variant	Exon 3 of 16	ENST00000470157.2	NP_001364925.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PPEF1	ENST00000470157.2	c.222T>A	p.His74Gln	missense_variant	Exon 3 of 16	3	NM_001377996.1	ENSP00000419273.2

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 26

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 24, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.222T>A (p.H74Q) alteration is located in exon 6 (coding exon 3) of the PPEF1 gene. This alteration results from a T to A substitution at nucleotide position 222, causing the histidine (H) at amino acid position 74 to be replaced by a glutamine (Q). 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	0.086
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-1.1
CADD	Benign	0.017
DANN	Benign	0.57
DEOGEN2	Benign	0.081	T;.
FATHMM_MKL	Benign	0.024	N
LIST_S2	Benign	0.17	T;T
M_CAP	Benign	0.045	D
MetaRNN	Benign	0.066	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N;N
PhyloP100		-1.5
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.42	N;N
REVEL	Benign	0.13
Sift	Benign	0.61	T;T
Sift4G	Benign	0.39	T;T
Polyphen		0.021	B;B
Vest4		0.047
MutPred		0.22		Loss of ubiquitination at K75 (P = 0.1343);Loss of ubiquitination at K75 (P = 0.1343);
MVP		0.22
MPC		0.50
ClinPred		0.041	T
GERP RS		-6.6
Varity_R		0.044
gMVP		0.27
Mutation Taster		=91/9	polymorphism

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

Other links and lift over

hg19: chrX-18751913; COSMIC: COSV62995225;