NM_001377996.1:c.584C>T

Variant names:

• chrX-18779035-C-T
• rs2046028908
• NM_001377996.1:c.584C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_001377996.1(PPEF1):​c.584C>T​(p.Pro195Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000025 in 1,199,592 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. 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. P195R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000090 (0 hom., 0 hem., cov: 22)
  • Exomes 𝑓: 0.0000018 (0 hom. 2 hem.)
• Consequence: PPEF1 NM_001377996.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.10
• 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 -4 ACMG points.

• BS2: High Hemizygotes in GnomAdExome4 at 2 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001377996.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPEF1	NM_001377996.1	MANE Select	c.584C>T	p.Pro195Leu	missense	Exon 7 of 16	NP_001364925.1	O14829-1
	PPEF1	NM_001377986.2		c.584C>T	p.Pro195Leu	missense	Exon 12 of 21	NP_001364915.1	O14829-1
	PPEF1	NM_001377993.1		c.584C>T	p.Pro195Leu	missense	Exon 9 of 18	NP_001364922.1	O14829-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPEF1	ENST00000470157.2	TSL:3 MANE Select	c.584C>T	p.Pro195Leu	missense	Exon 7 of 16	ENSP00000419273.2	O14829-1
	PPEF1	ENST00000361511.9	TSL:1	c.584C>T	p.Pro195Leu	missense	Exon 13 of 22	ENSP00000354871.3	O14829-1
	PPEF1	ENST00000471570.6	TSL:3	c.584C>T	p.Pro195Leu	missense	Exon 8 of 17	ENSP00000509623.1	O14829-1

Frequencies

GnomAD3 genomes AF: 0.00000900 AC: 1 AN: 111168 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.0000327

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000184 AC: 2 AN: 1088424 Hom.: 0 Cov.: 29 AF XY: 0.00000561 AC XY: 2 AN XY: 356290

African (AFR) AF: 0.00 AC: 0 AN: 26175

American (AMR) AF: 0.00 AC: 0 AN: 35144

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19293

East Asian (EAS) AF: 0.00 AC: 0 AN: 30163

South Asian (SAS) AF: 0.0000187 AC: 1 AN: 53615

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40492

Middle Eastern (MID) AF: 0.000243 AC: 1 AN: 4116

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 833640

Other (OTH) AF: 0.00 AC: 0 AN: 45786

GnomAD4 genome AF: 0.00000900 AC: 1 AN: 111168 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 33364

African (AFR) AF: 0.0000327 AC: 1 AN: 30550

American (AMR) AF: 0.00 AC: 0 AN: 10426

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2639

East Asian (EAS) AF: 0.00 AC: 0 AN: 3558

South Asian (SAS) AF: 0.00 AC: 0 AN: 2587

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5941

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53045

Other (OTH) AF: 0.00 AC: 0 AN: 1505

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	0.0052	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.78	D
FATHMM_MKL	Benign	0.24	N
LIST_S2	Benign	0.74	T
M_CAP	Uncertain	0.10	D
MetaRNN	Uncertain	0.46	T
MetaSVM	Uncertain	0.15	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		1.1
PrimateAI	Benign	0.30	T
PROVEAN	Pathogenic	-6.7	D
REVEL	Uncertain	0.35
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.019	D
Polyphen		1.0	D
Vest4		0.22
MutPred		0.45		Loss of disorder (P = 0.0377)
MVP		0.54
MPC		0.90
ClinPred		0.96	D
GERP RS		3.1
Varity_R		0.26
gMVP		0.85
Mutation Taster		=85/15	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

dbSNP: rs2046028908; hg19: chrX-18797153; COSMIC: COSV100583461;