Genetic Variant PIN4:p.Pro3Leu (chrX-72181793-C-T) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_006223.4(PIN4):c.8C>T(p.Pro3Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000139 in 1,078,213 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 6 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 24)

Exomes 𝑓: 0.000014 ( 0 hom. 6 hem. )

Consequence

PIN4
NM_006223.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.24

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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BS2

High Hemizygotes in GnomAdExome4 at 6 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIN4	NM_006223.4 link	c.8C>T	p.Pro3Leu	missense_variant	Exon 1 of 4	ENST00000373669.8	NP_006214.3	Q9Y237-1
PIN4	NM_001170747.1 link	c.83C>T	p.Pro28Leu	missense_variant	Exon 1 of 4		NP_001164218.1	Q9Y237-3
PIN4	NR_033187.2 link	n.37C>T		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.8C>T	p.Pro3Leu	missense_variant	Exon 1 of 4	1	NM_006223.4	ENSP00000362773.3		Q9Y237-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000113

AC:

AN:

176242

AF XY:

0.0000163

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000257

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000139

AC:

AN:

1078213

Hom.:

Cov.:

AF XY:

0.0000174

AC XY:

AN XY:

345443

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26144

American (AMR)

AF:

0.00

AC:

AN:

34922

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19244

East Asian (EAS)

AF:

0.00

AC:

AN:

30152

South Asian (SAS)

AF:

0.00

AC:

AN:

53200

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40373

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3736

European-Non Finnish (NFE)

AF:

0.0000182

AC:

AN:

824993

Other (OTH)

AF:

0.00

AC:

AN:

45449

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 21, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.83C>T (p.P28L) alteration is located in exon 1 (coding exon 1) of the PIN4 gene. This alteration results from a C to T substitution at nucleotide position 83, causing the proline (P) at amino acid position 28 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

Uncertain

0.46

BayesDel_addAF

Pathogenic

0.22

BayesDel_noAF

Uncertain

0.070

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.34

T;.;.;T

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.86

.;D;D;.

M_CAP

Uncertain

0.27

MetaRNN

Uncertain

0.44

T;T;T;T

MetaSVM

Uncertain

-0.042

PhyloP100

3.2

PrimateAI

Benign

0.46

PROVEAN

Pathogenic

-5.2

D;D;D;D

REVEL

Benign

0.29

Sift

Uncertain

0.0010

D;D;D;D

Sift4G

Uncertain

0.039

D;D;D;T

Polyphen

1.0

.;.;D;.

Vest4

0.37

MutPred

0.26

Loss of glycosylation at P28 (P = 0.0044);Loss of glycosylation at P28 (P = 0.0044);Loss of glycosylation at P28 (P = 0.0044);.;

MVP

0.57

MPC

0.45

ClinPred

0.98

GERP RS

5.3

PromoterAI

-0.055

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

gMVP

0.71

Mutation Taster

=89/11

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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X-72181793-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over