X-18783962-A-G

Variant names:

• chrX-18783962-A-G
• rs2046148316
• NM_001377996.1:c.826A>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001377996.1(PPEF1):​c.826A>G​(p.Ile276Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000746 in 1,206,290 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. 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 (★).

• Frequency:
  • Genomes: 𝑓 0.0000089 (0 hom., 0 hem., cov: 22)
  • Exomes 𝑓: 0.0000073 (0 hom. 1 hem.)
• Consequence: PPEF1 NM_001377996.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.803
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.42234305).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPEF1	NM_001377996.1	c.826A>G	p.Ile276Val	missense_variant	Exon 9 of 16	ENST00000470157.2	NP_001364925.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PPEF1	ENST00000470157.2	c.826A>G	p.Ile276Val	missense_variant	Exon 9 of 16	3	NM_001377996.1	ENSP00000419273.2

Frequencies

GnomAD3 genomes AF: 0.00000894 AC: 1 AN: 111873 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000188

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000731 AC: 8 AN: 1094417 Hom.: 0 Cov.: 29 AF XY: 0.00000278 AC XY: 1 AN XY: 359933

African (AFR) AF: 0.00 AC: 0 AN: 26304

American (AMR) AF: 0.00 AC: 0 AN: 35095

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19337

East Asian (EAS) AF: 0.00 AC: 0 AN: 30171

South Asian (SAS) AF: 0.00 AC: 0 AN: 53851

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40527

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4134

European-Non Finnish (NFE) AF: 0.00000953 AC: 8 AN: 839022

Other (OTH) AF: 0.00 AC: 0 AN: 45976

GnomAD4 genome AF: 0.00000894 AC: 1 AN: 111873 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 34025

African (AFR) AF: 0.00 AC: 0 AN: 30774

American (AMR) AF: 0.00 AC: 0 AN: 10573

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2654

East Asian (EAS) AF: 0.00 AC: 0 AN: 3574

South Asian (SAS) AF: 0.00 AC: 0 AN: 2690

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5973

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 238

European-Non Finnish (NFE) AF: 0.0000188 AC: 1 AN: 53203

Other (OTH) AF: 0.00 AC: 0 AN: 1508

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 08, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.826A>G (p.I276V) alteration is located in exon 12 (coding exon 9) of the PPEF1 gene. This alteration results from a A to G substitution at nucleotide position 826, causing the isoleucine (I) at amino acid position 276 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	0.065
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.46
DANN	Benign	0.21
DEOGEN2	Uncertain	0.43	T;.;.
FATHMM_MKL	Benign	0.092	N
LIST_S2	Benign	0.61	T;T;T
M_CAP	Benign	0.0087	T
MetaRNN	Benign	0.42	T;T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.3	L;L;.
PhyloP100		0.80
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.75	N;N;N
REVEL	Benign	0.061
Sift	Benign	0.20	T;T;T
Sift4G	Benign	0.42	T;T;T
Polyphen		0.0010	B;B;.
Vest4		0.13
MutPred		0.88		Loss of sheet (P = 0.1398);Loss of sheet (P = 0.1398);.;
MVP		0.16
MPC		0.42
ClinPred		0.063	T
GERP RS		-0.36
Varity_R		0.088
gMVP		0.52
Mutation Taster		=96/4	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

dbSNP: rs2046148316; hg19: chrX-18802080;