Genetic Variant NM_004792.3:c.122G>A (chr2-169604247-G-A) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_004792.3(PPIG):c.122G>A(p.Arg41His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,456,848 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

PPIG
NM_004792.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.61

Variant links:

Genes affected

PPIG (HGNC:14650): (peptidylprolyl isomerase G) Enables cyclosporin A binding activity and peptidyl-prolyl cis-trans isomerase activity. Involved in protein peptidyl-prolyl isomerization. Located in cytosol and nuclear speck. [provided by Alliance of Genome Resources, Apr 2022]

PPIG links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.92

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPIG	NM_004792.3 link	c.122G>A	p.Arg41His	missense_variant	Exon 4 of 14	ENST00000260970.8	NP_004783.2	Q13427-1
PPIG	XM_005246966.3 link	c.122G>A	p.Arg41His	missense_variant	Exon 4 of 14		XP_005247023.1	Q13427-1
PPIG	XM_005246967.2 link	c.122G>A	p.Arg41His	missense_variant	Exon 4 of 14		XP_005247024.1	Q13427-1
PPIG	XM_017005302.3 link	c.122G>A	p.Arg41His	missense_variant	Exon 4 of 12		XP_016860791.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PPIG	ENST00000260970.8 link	c.122G>A	p.Arg41His	missense_variant	Exon 4 of 14	1	NM_004792.3	ENSP00000260970.3		Q13427-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.86e-7

AC:

AN:

1456848

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

724778

show subpopulations

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:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 28, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.122G>A (p.R41H) alteration is located in exon 4 (coding exon 2) of the PPIG gene. This alteration results from a G to A substitution at nucleotide position 122, causing the arginine (R) at amino acid position 41 to be replaced by a histidine (H). 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

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Uncertain

0.010

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.26

T;T;.;T;T;T

Eigen

Pathogenic

0.95

Eigen_PC

Pathogenic

0.88

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.97

.;D;D;D;D;D

M_CAP

Benign

0.048

MetaRNN

Pathogenic

0.92

D;D;D;D;D;D

MetaSVM

Benign

-0.47

MutationAssessor

Uncertain

2.8

M;.;M;M;.;.

PrimateAI

Pathogenic

0.80

PROVEAN

Uncertain

-3.0

D;D;D;D;D;D

REVEL

Uncertain

0.46

Sift

Uncertain

0.0030

D;D;D;D;D;D

Sift4G

Benign

0.076

T;T;D;T;D;D

Polyphen

1.0

D;D;D;D;.;.

Vest4

0.89

MutPred

0.82

Gain of catalytic residue at C42 (P = 0.1306);Gain of catalytic residue at C42 (P = 0.1306);Gain of catalytic residue at C42 (P = 0.1306);Gain of catalytic residue at C42 (P = 0.1306);Gain of catalytic residue at C42 (P = 0.1306);Gain of catalytic residue at C42 (P = 0.1306);

MVP

0.53

MPC

2.2

ClinPred

0.96

GERP RS

5.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.68

gMVP

0.81

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over