X-18733794-A-G

Variant names:

• chrX-18733794-A-G
• NM_001377996.1:c.221A>G

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.221A>G​(p.His74Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000187 in 1,071,410 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H74Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000019 (0 hom. 1 hem.)
• Consequence: PPEF1 NM_001377996.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.95
• 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=0.064713836).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPEF1	NM_001377996.1	c.221A>G	p.His74Arg	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.221A>G	p.His74Arg	missense_variant	Exon 3 of 16	3	NM_001377996.1	ENSP00000419273.2

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000187 AC: 2 AN: 1071410 Hom.: 0 Cov.: 26 AF XY: 0.00000291 AC XY: 1 AN XY: 343760

African (AFR) AF: 0.00 AC: 0 AN: 25317

American (AMR) AF: 0.00 AC: 0 AN: 30630

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18562

East Asian (EAS) AF: 0.00 AC: 0 AN: 29503

South Asian (SAS) AF: 0.00 AC: 0 AN: 49813

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39815

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3881

European-Non Finnish (NFE) AF: 0.00000241 AC: 2 AN: 828897

Other (OTH) AF: 0.00 AC: 0 AN: 44992

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 05, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.221A>G (p.H74R) alteration is located in exon 6 (coding exon 3) of the PPEF1 gene. This alteration results from a A to G substitution at nucleotide position 221, causing the histidine (H) at amino acid position 74 to be replaced by an arginine (R). 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	0.061
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-1.2
CADD	Benign	0.0010
DANN	Benign	0.16
DEOGEN2	Benign	0.098	T;.
FATHMM_MKL	Benign	0.018	N
LIST_S2	Benign	0.19	T;T
M_CAP	Benign	0.0026	T
MetaRNN	Benign	0.065	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.69	N;N
PhyloP100		-1.9
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.49	N;N
REVEL	Benign	0.010
Sift	Benign	0.56	T;T
Sift4G	Benign	0.43	T;T
Polyphen		0.0010	B;B
Vest4		0.033
MutPred		0.31		Gain of helix (P = 0.062);Gain of helix (P = 0.062);
MVP		0.20
MPC		0.60
ClinPred		0.060	T
GERP RS		-11
Varity_R		0.035
gMVP		0.27
Mutation Taster		=90/10	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-18751912;