X-18757640-A-G

Variant names:

• chrX-18757640-A-G
• rs773375576
• NM_001377996.1:c.410A>G

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001377996.1(PPEF1):​c.410A>G​(p.His137Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000307 in 1,203,453 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 11 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 0.000027 (0 hom., 2 hem., cov: 22)
  • Exomes 𝑓: 0.000031 (0 hom. 9 hem.)
• Consequence: PPEF1 NM_001377996.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.71
• 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 -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.06829819).
• BS2: High Hemizygotes in GnomAd4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPEF1	NM_001377996.1	c.410A>G	p.His137Arg	missense_variant	Exon 5 of 16	ENST00000470157.2	NP_001364925.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PPEF1	ENST00000470157.2	c.410A>G	p.His137Arg	missense_variant	Exon 5 of 16	3	NM_001377996.1	ENSP00000419273.2

Frequencies

GnomAD3 genomes AF: 0.0000268 AC: 3 AN: 111794 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.0000326

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: 0.0000376

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000385 AC: 7 AN: 181594 AF XY: 0.0000151

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000186

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000123

Gnomad OTH exome AF: 0.000224

GnomAD4 exome AF: 0.0000311 AC: 34 AN: 1091659 Hom.: 0 Cov.: 27 AF XY: 0.0000252 AC XY: 9 AN XY: 357381

African (AFR) AF: 0.0000380 AC: 1 AN: 26289

American (AMR) AF: 0.000256 AC: 9 AN: 35089

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19324

East Asian (EAS) AF: 0.00 AC: 0 AN: 30162

South Asian (SAS) AF: 0.00 AC: 0 AN: 53644

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40481

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4118

European-Non Finnish (NFE) AF: 0.0000263 AC: 22 AN: 836666

Other (OTH) AF: 0.0000436 AC: 2 AN: 45886

GnomAD4 genome AF: 0.0000268 AC: 3 AN: 111794 Hom.: 0 Cov.: 22 AF XY: 0.0000588 AC XY: 2 AN XY: 33992

African (AFR) AF: 0.0000326 AC: 1 AN: 30697

American (AMR) AF: 0.00 AC: 0 AN: 10515

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2647

East Asian (EAS) AF: 0.00 AC: 0 AN: 3565

South Asian (SAS) AF: 0.00 AC: 0 AN: 2658

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6050

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

European-Non Finnish (NFE) AF: 0.0000376 AC: 2 AN: 53230

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

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000869

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 09, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.410A>G (p.H137R) alteration is located in exon 8 (coding exon 5) of the PPEF1 gene. This alteration results from a A to G substitution at nucleotide position 410, causing the histidine (H) at amino acid position 137 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	0.060
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.91
CADD	Benign	3.3
DANN	Benign	0.26
DEOGEN2	Benign	0.051	T;.;T
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.66	T;T;T
M_CAP	Benign	0.0037	T
MetaRNN	Benign	0.068	T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.17	N;N;.
PhyloP100		1.7
PrimateAI	Benign	0.26	T
PROVEAN	Benign	0.97	N;N;N
REVEL	Benign	0.040
Sift	Benign	1.0	T;T;T
Sift4G	Benign	1.0	T;T;T
Polyphen		0.0	B;B;.
Vest4		0.070
MutPred		0.43		Gain of solvent accessibility (P = 0.0374);Gain of solvent accessibility (P = 0.0374);.;
MVP		0.16
MPC		0.60
ClinPred		0.013	T
GERP RS		1.0
Varity_R		0.045
gMVP		0.45
Mutation Taster		=99/1	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: rs773375576; hg19: chrX-18775758;