2-200881452-T-C

Variant summary

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

The NM_130906.3(PPIL3):c.209A>G(p.Lys70Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000547 in 1,461,226 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: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: PPIL3 NM_130906.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.83

Genes affected

PPIL3 (HGNC:9262): (peptidylprolyl isomerase like 3) This gene encodes a member of the cyclophilin family. Cyclophilins catalyze the cis-trans isomerization of peptidylprolyl imide bonds in oligopeptides. They have been proposed to act either as catalysts or as molecular chaperones in protein-folding events. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 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=0.28861916).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PPIL3	NM_130906.3	c.209A>G	p.Lys70Arg	missense_variant	5/7	ENST00000392283.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PPIL3	ENST00000392283.9	c.209A>G	p.Lys70Arg	missense_variant	5/7	1	NM_130906.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000797 AC: 2 AN: 250994 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135686

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461226 Hom.: 0 Cov.: 29 AF XY: 0.00000413 AC XY: 3 AN XY: 726930

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000757

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000468 Hom.: 0

Asia WGS AF: 0.000289 AC: 1 AN: 3478

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

Sep 20, 2023

The c.221A>G (p.K74R) alteration is located in exon 5 (coding exon 4) of the PPIL3 gene. This alteration results from a A to G substitution at nucleotide position 221, causing the lysine (K) 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	0.084
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.33
Cadd	Uncertain	24
Dann	Uncertain	0.99
Eigen	Benign	0.049
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Benign	0.040	D
MetaRNN	Benign	0.29	T;T;T;T;T;T
MetaSVM	Benign	-0.92	T
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-1.6	N;N;N;N;N;N
REVEL	Benign	0.16
Sift	Benign	0.10	T;T;T;T;T;T
Sift4G	Benign	0.37	T;T;T;T;T;T
Polyphen		0.053	B;B;.;.;B;.
Vest4		0.61
MutPred		0.33		.;Loss of methylation at K70 (P = 0.0012);.;.;.;Loss of methylation at K70 (P = 0.0012);
MVP		0.54
MPC		0.23
ClinPred		0.35	T
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.56
gMVP		0.082

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: rs1163717502; hg19: chr2-201746175;