Genetic Variant PIN4:p.Ala12Pro (chrX-72181819-G-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_006223.4(PIN4):c.34G>C(p.Ala12Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000966 in 1,035,181 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A12T) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 24)

Exomes 𝑓: 9.7e-7 ( 0 hom. 0 hem. )

Consequence

PIN4
NM_006223.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.54

Publications

0 publications found

Variant links:

Genes affected

PIN4 (HGNC:8992): (peptidylprolyl cis/trans isomerase, NIMA-interacting 4) This gene encodes a member of the parvulin subfamily of the peptidyl-prolyl cis/trans isomerase protein family. The encoded protein catalyzes the isomerization of peptidylprolyl bonds, and may play a role in the cell cycle, chromatin remodeling, and/or ribosome biogenesis. The encoded protein may play an additional role in the mitochondria. [provided by RefSeq, Dec 2009]

PIN4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.11293253).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIN4	NM_006223.4 link	c.34G>C	p.Ala12Pro	missense_variant	Exon 1 of 4	ENST00000373669.8	NP_006214.3	Q9Y237-1
PIN4	NM_001170747.1 link	c.109G>C	p.Ala37Pro	missense_variant	Exon 1 of 4		NP_001164218.1	Q9Y237-3
PIN4	NR_033187.2 link	n.63G>C		non_coding_transcript_exon_variant	Exon 1 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PIN4	ENST00000373669.8 link	c.34G>C	p.Ala12Pro	missense_variant	Exon 1 of 4	1	NM_006223.4	ENSP00000362773.3		Q9Y237-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

9.66e-7

AC:

AN:

1035181

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

309727

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

25553

American (AMR)

AF:

0.00

AC:

AN:

33798

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18868

East Asian (EAS)

AF:

0.00

AC:

AN:

29879

South Asian (SAS)

AF:

0.00

AC:

AN:

51546

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39941

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3822

European-Non Finnish (NFE)

AF:

0.00000127

AC:

AN:

787714

Other (OTH)

AF:

0.00

AC:

AN:

44060

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.40

CADD

Uncertain

(source)

DANN

Benign

0.88

DEOGEN2

Benign

0.064

T;.;.;T

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.34

.;T;T;.

M_CAP

Benign

0.028

MetaRNN

Benign

0.11

T;T;T;T

MetaSVM

Benign

-0.83

PhyloP100

2.5

PrimateAI

Benign

0.38

PROVEAN

Benign

-1.2

N;N;N;N

REVEL

Benign

0.063

Sift

Benign

0.074

T;D;T;D

Sift4G

Benign

0.096

T;T;T;T

Polyphen

0.12

.;.;B;.

Vest4

0.25

MutPred

0.18

Loss of MoRF binding (P = 0.0606);Loss of MoRF binding (P = 0.0606);Loss of MoRF binding (P = 0.0606);.;

MVP

0.27

MPC

0.17

ClinPred

0.30

GERP RS

4.2

PromoterAI

0.16

Neutral

(source)

gMVP

0.53

Mutation Taster

=75/25

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over