10-79352382-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_005729.4(PPIF):c.478A>G(p.Lys160Glu) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,461,626 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: PPIF NM_005729.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.34

Genes affected

PPIF (HGNC:9259): (peptidylprolyl isomerase F) The protein encoded by this gene is a member of the peptidyl-prolyl cis-trans isomerase (PPIase) family. PPIases catalyze the cis-trans isomerization of proline imidic peptide bonds in oligopeptides and accelerate the folding of proteins. This protein is part of the mitochondrial permeability transition pore in the inner mitochondrial membrane. Activation of this pore is thought to be involved in the induction of apoptotic and necrotic cell death. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.32477668).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PPIF	NM_005729.4	c.478A>G	p.Lys160Glu	missense_variant	5/6	ENST00000225174.8
PPIF	XM_005269379.3	c.478A>G	p.Lys160Glu	missense_variant	5/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PPIF	ENST00000225174.8	c.478A>G	p.Lys160Glu	missense_variant	5/6	1	NM_005729.4	P1
PPIF	ENST00000448165.1	c.370A>G	p.Lys124Glu	missense_variant	5/6	2
PPIF	ENST00000472580.6	c.*171A>G		3_prime_UTR_variant, NMD_transcript_variant	5/6	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000795 AC: 2 AN: 251446 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135896

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461626 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 727144

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000329 Hom.: 0

Bravo AF: 0.0000113

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 26, 2022

The c.478A>G (p.K160E) alteration is located in exon 5 (coding exon 5) of the PPIF gene. This alteration results from a A to G substitution at nucleotide position 478, causing the lysine (K) at amino acid position 160 to be replaced by a glutamic acid (E). 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	Uncertain	0.34
BayesDel_addAF	Benign	-0.085	T
BayesDel_noAF	Benign	-0.34
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Benign	0.22	T
Eigen	Benign	0.014
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.32	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.20	N
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-2.9	D
REVEL	Benign	0.15
Sift	Uncertain	0.025	D
Sift4G	Uncertain	0.055	T
Polyphen		0.0030	B
Vest4		0.52
MVP		0.67
MPC		0.065
ClinPred		0.46	T
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.81
gMVP		0.60

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

Publications

LitVar

Other links and lift over

dbSNP: rs370573857; hg19: chr10-81112138;