6-36855935-T-C

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 6P and 1B. PM1PM2PP2PP5BP4

The NM_016059.5(PPIL1):c.379A>G(p.Thr127Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0000514 in 1,614,078 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000055 ( 0 hom. )

Consequence

PPIL1
NM_016059.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4U:1

Conservation

PhyloP100: 6.02

Publications

3 publications found

Variant links:

Genes affected

PPIL1 (HGNC:9260): (peptidylprolyl isomerase like 1) This gene is a member of the cyclophilin family of peptidylprolyl isomerases (PPIases). The cyclophilins are a highly conserved, ubiquitous family, members of which play an important role in protein folding, immunosuppression by cyclosporin A, and infection of HIV-1 virions. Based on similarity to other PPIases, this protein could accelerate the folding of proteins and might catalyze the cis-trans isomerization of proline imidic peptide bonds in oligopeptides. [provided by RefSeq, Jul 2008]

PPIL1 Gene-Disease associations (from GenCC):

pontocerebellar hypoplasia, type 14
Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Broad Center for Mendelian Genomics, Ambry Genetics

PPIL1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

PM1

In a domain PPIase cyclophilin-type (size 154) in uniprot entity PPIL1_HUMAN there are 7 pathogenic changes around while only 0 benign (100%) in NM_016059.5

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 6 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 0.5799 (below the threshold of 3.09). Trascript score misZ: 0.88366 (below the threshold of 3.09). GenCC associations: The gene is linked to pontocerebellar hypoplasia, type 14.

PP5

Variant 6-36855935-T-C is Pathogenic according to our data. Variant chr6-36855935-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 930026.We mark this variant Likely_pathogenic, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

BP4

Computational evidence support a benign effect (MetaRNN=0.17045751). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPIL1	NM_016059.5 link	c.379A>G	p.Thr127Ala	missense_variant	Exon 4 of 4	ENST00000373699.6	NP_057143.1	Q9Y3C6A0A024RCX8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PPIL1	ENST00000373699.6 link	c.379A>G	p.Thr127Ala	missense_variant	Exon 4 of 4	1	NM_016059.5	ENSP00000362803.5		Q9Y3C6
PPIL1	ENST00000483552.1 link	n.239A>G		non_coding_transcript_exon_variant	Exon 3 of 3	2

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152068

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000835

AC:

AN:

251416

AF XY:

0.0000662

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000150

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000547

AC:

AN:

1461892

Hom.:

Cov.:

AF XY:

0.0000619

AC XY:

AN XY:

727246

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.0000671

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.000347

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000674

AC:

AN:

1112012

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152186

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74390

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41532

American (AMR)

AF:

0.0000654

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.00

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10592

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

67992

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.542

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000762

Hom.:

Bravo

AF:

0.0000264

ExAC

AF:

0.000107

AC:

EpiCase

AF:

0.000273

EpiControl

AF:

0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Pontocerebellar hypoplasia, type 14

Pathogenic:2

Apr 30, 2021

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Aug 05, 2025

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Low frequency in gnomAD population databases (PM2_sup). Variant is located in a mutational hotspot (PM1_mod). Detected in trans with a pathogenic variant in an affected case (PM3_s). -

Congenital pontocerebellar hypoplasia

Pathogenic:1

Jan 20, 2021

Yale Center for Mendelian Genomics, Yale University

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

not provided

Pathogenic:1

Dec 11, 2024

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Published functional studies demonstrate a damaging effect of decreased protein level (PMID: 33220177); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 33220177) -

not specified

Uncertain:1

May 02, 2019

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant classified as Uncertain Significance - Favor Pathogenic. The p.Thr127Ala variant was identified with a canonical splice variant (phase not determined) in another family with two relatives with a neurodevelopmental phenotype consisting of profound global developmental delays, abnormal muscle tone, and intractable seizures (Gleeson et al, unpublished data). It was also identified in this family in a compound heterozygous state with a loss of function variant in two siblings with profound global developmental delays, microcephaly, intractable seizures, hypotonia, hypoplasia of the corpus callosum, and cortical vision impairment by the Broad Institute Rare Genomes Project. In vitro functional studies of p.Thr127Ala demonstrate a reduction of protein levels in cultured cells (Joseph Gleeson laboratory, UC San Diego, unpublished data) although this observation may not represent disrupted biological function. This variant has been identified in 0.014% of non-Finnish European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org). Computational prediction tools and amino acid conservation analysis suggest that the p.Thr127Ala variant may impact the protein, though this information is not predictive enough to determine pathogenicity through a protein sequence change. Currently, there is moderate evidence to support an association between PPIL1 and a severe neurodevelopmental phenotype. In summary, while there is suspicion for a pathogenic role, the clinical significance of the p.Thr127Ala variant remains uncertain. ACMG/AMP Criteria applied: PS3_Moderate, PM2_Supporting, PP3. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.29

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.33

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.042

Eigen

Benign

0.039

Eigen_PC

Benign

0.22

FATHMM_MKL

Uncertain

0.89

LIST_S2

Uncertain

0.87

M_CAP

Benign

0.010

MetaRNN

Benign

0.17

MetaSVM

Benign

-1.1

MutationAssessor

Benign

2.0

PhyloP100

6.0

PrimateAI

Uncertain

0.64

PROVEAN

Uncertain

-4.3

REVEL

Benign

0.12

Sift

Benign

0.034

Sift4G

Benign

0.087

Polyphen

0.0010

Vest4

0.46

MVP

0.30

MPC

0.35

ClinPred

0.20

GERP RS

5.5

Varity_R

0.68

gMVP

0.63

Mutation Taster

=59/41

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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6-36855935-T-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over