19-9835367-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP3BS2

The NM_006221.4(PIN1):c.23C>T(p.Pro8Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00011 in 1,521,278 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P8S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

PIN1
NM_006221.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.55

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 Likely_benign. Variant got -3 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.832

BS2

High AC in GnomAd at 20 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
PIN1	NM_006221.4 linkuse as main transcript	c.23C>T	p.Pro8Leu	missense_variant	1/4	ENST00000247970.9
PIN1	XM_011528068.3 linkuse as main transcript	c.-80C>T		5_prime_UTR_variant	1/6
PIN1	NR_038422.3 linkuse as main transcript	n.50C>T		non_coding_transcript_exon_variant	1/5
PIN1	NR_038830.2 linkuse as main transcript	n.50C>T		non_coding_transcript_exon_variant	1/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PIN1	ENST00000247970.9 linkuse as main transcript	c.23C>T	p.Pro8Leu	missense_variant	1/4	1	NM_006221.4	P1

Frequencies

GnomAD3 genomes

AF:

0.000132

AC:

AN:

151980

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000966

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.000235

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000339

AC:

AN:

117886

Hom.:

AF XY:

0.0000462

AC XY:

AN XY:

64990

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000893

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000108

AC:

148

AN:

1369298

Hom.:

Cov.:

AF XY:

0.000101

AC XY:

AN XY:

675660

show subpopulations

Gnomad4 AFR exome

AF:

0.000138

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000125

Gnomad4 OTH exome

AF:

0.000175

GnomAD4 genome

AF:

0.000132

AC:

AN:

151980

Hom.:

Cov.:

AF XY:

0.0000674

AC XY:

AN XY:

74238

show subpopulations

Gnomad4 AFR

AF:

0.0000966

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000235

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000131

Hom.:

Bravo

AF:

0.000106

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

Dec 06, 2022

The c.23C>T (p.P8L) alteration is located in exon 1 (coding exon 1) of the PIN1 gene. This alteration results from a C to T substitution at nucleotide position 23, causing the proline (P) at amino acid position 8 to be replaced by a leucine (L). 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

0.92

BayesDel_addAF

Pathogenic

0.26

BayesDel_noAF

Uncertain

0.13

Cadd

Pathogenic

Dann

Uncertain

1.0

DEOGEN2

Uncertain

0.77

D;D;D

Eigen

Pathogenic

0.84

Eigen_PC

Pathogenic

0.74

FATHMM_MKL

Uncertain

0.85

LIST_S2

Pathogenic

0.98

D;.;D

M_CAP

Pathogenic

0.85

MetaRNN

Pathogenic

0.83

D;D;D

MetaSVM

Pathogenic

1.1

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.74

Sift4G

Pathogenic

0.0010

D;D;D

Polyphen

1.0

.;D;D

Vest4

0.57

MutPred

0.69

Loss of disorder (P = 0.0436);Loss of disorder (P = 0.0436);Loss of disorder (P = 0.0436);

MVP

0.97

MPC

1.7

ClinPred

0.99

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.91

gMVP

0.90

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

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