Variant 19-9838491-C-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_006221.4(PIN1):c.114C>A(p.Ser38Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000755 in 1,456,590 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000076 ( 0 hom. )

Consequence

PIN1
NM_006221.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -2.88

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:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.17258811).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
PIN1	NM_006221.4 linkuse as main transcript	c.114C>A	p.Ser38Arg	missense_variant	2/4	ENST00000247970.9
PIN1	XM_011528068.3 linkuse as main transcript	c.129C>A	p.Ser43Arg	missense_variant	4/6
PIN1	NR_038422.3 linkuse as main transcript	n.194C>A		non_coding_transcript_exon_variant	3/5
PIN1	NR_038830.2 linkuse as main transcript	n.194C>A		non_coding_transcript_exon_variant	3/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PIN1	ENST00000247970.9 linkuse as main transcript	c.114C>A	p.Ser38Arg	missense_variant	2/4	1	NM_006221.4	P1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000419

AC:

AN:

238604

Hom.:

AF XY:

0.00

AC XY:

AN XY:

129406

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:

0.00000926

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000755

AC:

AN:

1456590

Hom.:

Cov.:

AF XY:

0.00000552

AC XY:

AN XY:

724066

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000991

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

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

Sep 06, 2022

The c.114C>A (p.S38R) alteration is located in exon 2 (coding exon 2) of the PIN1 gene. This alteration results from a C to A substitution at nucleotide position 114, causing the serine (S) at amino acid position 38 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

Uncertain

0.52

BayesDel_addAF

Benign

-0.076

BayesDel_noAF

Benign

-0.35

Cadd

Benign

0.43

Dann

Benign

0.97

DEOGEN2

Benign

0.39

T;T;T

Eigen

Benign

-0.99

Eigen_PC

Benign

-0.99

FATHMM_MKL

Benign

0.088

LIST_S2

Benign

0.73

T;.;T

M_CAP

Uncertain

0.10

MetaRNN

Benign

0.17

T;T;T

MetaSVM

Benign

-0.80

MutationTaster

Benign

0.68

N;N;N

PrimateAI

Uncertain

0.68

Sift4G

Benign

0.18

T;T;T

Polyphen

0.60

.;P;P

Vest4

0.33

MutPred

0.28

Loss of phosphorylation at S38 (P = 0.0113);Loss of phosphorylation at S38 (P = 0.0113);Loss of phosphorylation at S38 (P = 0.0113);

MVP

0.70

MPC

0.79

ClinPred

0.51

GERP RS

-2.5

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.7

Varity_R

0.42

gMVP

0.45

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