19-9849126-C-T

Variant summary

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

The NM_006221.4(PIN1):c.419C>T(p.Ala140Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000124 in 1,613,682 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: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

PIN1
NM_006221.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.82

Variant links:

Genes affected

PIN1 (HGNC:8988): (peptidylprolyl cis/trans isomerase, NIMA-interacting 1) Peptidyl-prolyl cis/trans isomerases (PPIases) catalyze the cis/trans isomerization of peptidyl-prolyl peptide bonds. This gene encodes one of the PPIases, which specifically binds to phosphorylated ser/thr-pro motifs to catalytically regulate the post-phosphorylation conformation of its substrates. The conformational regulation catalyzed by this PPIase has a profound impact on key proteins involved in the regulation of cell growth, genotoxic and other stress responses, the immune response, induction and maintenance of pluripotency, germ cell development, neuronal differentiation, and survival. This enzyme also plays a key role in the pathogenesis of Alzheimer's disease and many cancers. Multiple alternatively spliced transcript variants have been found for this gene.[provided by RefSeq, Jun 2011]

PIN1 links:

Genome browser will be placed here

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, 0.867

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
PIN1	NM_006221.4 linkuse as main transcript	c.419C>T	p.Ala140Val	missense_variant	4/4	ENST00000247970.9
PIN1	XM_011528068.3 linkuse as main transcript	c.434C>T	p.Ala145Val	missense_variant	6/6
PIN1	NR_038422.3 linkuse as main transcript	n.499C>T		non_coding_transcript_exon_variant	5/5
PIN1	NR_038830.2 linkuse as main transcript	n.499C>T		non_coding_transcript_exon_variant	5/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PIN1	ENST00000247970.9 linkuse as main transcript	c.419C>T	p.Ala140Val	missense_variant	4/4	1	NM_006221.4	P1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152222

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461460

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727070

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

AF:

0.00000657

AC:

AN:

152222

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74364

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 02, 2023

The c.419C>T (p.A140V) alteration is located in exon 4 (coding exon 4) of the PIN1 gene. This alteration results from a C to T substitution at nucleotide position 419, causing the alanine (A) at amino acid position 140 to be replaced by a valine (V). 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

0.40

BayesDel_addAF

Uncertain

0.015

BayesDel_noAF

Benign

-0.22

Cadd

Uncertain

Dann

Pathogenic

1.0

DEOGEN2

Uncertain

0.58

D;D

Eigen

Uncertain

0.59

Eigen_PC

Uncertain

0.49

FATHMM_MKL

Uncertain

0.85

M_CAP

Benign

0.043

MetaRNN

Pathogenic

0.87

D;D

MetaSVM

Uncertain

-0.24

MutationAssessor

Uncertain

2.8

M;M

MutationTaster

Benign

1.0

D;D

PrimateAI

Pathogenic

0.80

PROVEAN

Uncertain

-3.2

D;.

REVEL

Uncertain

0.32

Sift

Uncertain

0.0030

D;.

Sift4G

Uncertain

0.0060

D;D

Polyphen

0.99

D;D

Vest4

0.78

MutPred

0.52

Loss of disorder (P = 0.0649);Loss of disorder (P = 0.0649);

MVP

0.78

MPC

1.1

ClinPred

0.96

GERP RS

4.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.54

gMVP

0.81

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over