Genetic Variant PPIA:p.Lys131Ile (chr7-44801316-A-T) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM1PM2BP4

The NM_021130.5(PPIA):c.392A>T(p.Lys131Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,002 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K131R) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

PPIA
NM_021130.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.618

Publications

0 publications found

Variant links:

Genes affected

PPIA (HGNC:9253): (peptidylprolyl isomerase A) This gene encodes 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. The encoded protein is a cyclosporin binding-protein and may play a role in cyclosporin A-mediated immunosuppression. The protein can also interact with several HIV proteins, including p55 gag, Vpr, and capsid protein, and has been shown to be necessary for the formation of infectious HIV virions. Multiple pseudogenes that map to different chromosomes have been reported. [provided by RefSeq, Jul 2008]

PPIA links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM1

In a modified_residue N6-acetyllysine (size 0) in uniprot entity PPIA_HUMAN

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.3488908).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPIA	NM_021130.5 link	c.392A>T	p.Lys131Ile	missense_variant	Exon 5 of 5	ENST00000468812.6	NP_066953.1	P62937-1V9HWF5
PPIA	NM_001300981.2 link	c.212A>T	p.Lys71Ile	missense_variant	Exon 6 of 6		NP_001287910.1	P62937-2
PPIA	XM_047420536.1 link	c.212A>T	p.Lys71Ile	missense_variant	Exon 6 of 6		XP_047276492.1
PPIA	XM_047420537.1 link	c.212A>T	p.Lys71Ile	missense_variant	Exon 6 of 6		XP_047276493.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PPIA	ENST00000468812.6 link	c.392A>T	p.Lys131Ile	missense_variant	Exon 5 of 5	1	NM_021130.5	ENSP00000419425.1		P62937-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461002

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726872

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33458

American (AMR)

AF:

0.00

AC:

AN:

44692

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26124

East Asian (EAS)

AF:

0.00

AC:

AN:

39694

South Asian (SAS)

AF:

0.00

AC:

AN:

86236

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53214

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5580

European-Non Finnish (NFE)

AF:

9.00e-7

AC:

AN:

1111662

Other (OTH)

AF:

0.00

AC:

AN:

60342

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.36

BayesDel_addAF

Benign

-0.073

BayesDel_noAF

Benign

-0.34

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.27

T;.;.;.

Eigen

Benign

-0.28

Eigen_PC

Benign

-0.31

FATHMM_MKL

Benign

0.33

LIST_S2

Benign

0.58

T;.;.;T

M_CAP

Benign

0.018

MetaRNN

Benign

0.35

T;T;T;T

MetaSVM

Benign

-0.80

MutationAssessor

Uncertain

2.6

M;.;.;.

PhyloP100

0.62

PrimateAI

Benign

0.41

PROVEAN

Pathogenic

-6.2

D;D;D;.

REVEL

Benign

0.11

Sift

Uncertain

0.0010

D;D;D;.

Sift4G

Uncertain

0.0060

D;D;D;D

Polyphen

0.029

B;.;.;.

Vest4

0.39

MutPred

0.37

Loss of methylation at K131 (P = 0.0061);.;.;.;

MVP

0.76

MPC

2.5

ClinPred

0.84

GERP RS

2.4

Varity_R

0.87

gMVP

0.74

Mutation Taster

=82/18

polymorphism

(source)

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

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7-44801316-A-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over