Genetic Variant PIN4:p.Gly5Arg (chrX-72181798-G-A) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_006223.4(PIN4):c.13G>A(p.Gly5Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000038 in 1,183,531 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 23 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000054 ( 0 hom., 1 hem., cov: 24)

Exomes 𝑓: 0.000036 ( 0 hom. 22 hem. )

Consequence

PIN4
NM_006223.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.06

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: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.057047695).

BS2

High Hemizygotes in GnomAdExome4 at 22 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIN4	NM_006223.4 link	c.13G>A	p.Gly5Arg	missense_variant	Exon 1 of 4	ENST00000373669.8	NP_006214.3	Q9Y237-1
PIN4	NM_001170747.1 link	c.88G>A	p.Gly30Arg	missense_variant	Exon 1 of 4		NP_001164218.1	Q9Y237-3
PIN4	NR_033187.2 link	n.42G>A		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.13G>A	p.Gly5Arg	missense_variant	Exon 1 of 4	1	NM_006223.4	ENSP00000362773.3		Q9Y237-1

Frequencies

GnomAD3 genomes

AF:

0.0000536

AC:

AN:

112021

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00227

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

GnomAD2 exomes

AF:

0.0000575

AC:

AN:

173899

AF XY:

0.0000842

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00137

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000364

AC:

AN:

1071510

Hom.:

Cov.:

AF XY:

0.0000648

AC XY:

AN XY:

339248

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26066

American (AMR)

AF:

0.00

AC:

AN:

34810

Ashkenazi Jewish (ASJ)

AF:

0.00172

AC:

AN:

19193

East Asian (EAS)

AF:

0.00

AC:

AN:

30120

South Asian (SAS)

AF:

0.00

AC:

AN:

52932

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40312

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3802

European-Non Finnish (NFE)

AF:

0.00000610

AC:

AN:

819041

Other (OTH)

AF:

0.0000221

AC:

AN:

45234

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

AF:

0.0000536

AC:

AN:

112021

Hom.:

Cov.:

AF XY:

0.0000293

AC XY:

AN XY:

34183

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30777

American (AMR)

AF:

0.00

AC:

AN:

10597

Ashkenazi Jewish (ASJ)

AF:

0.00227

AC:

AN:

2644

East Asian (EAS)

AF:

0.00

AC:

AN:

3561

South Asian (SAS)

AF:

0.00

AC:

AN:

2735

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6061

Middle Eastern (MID)

AF:

0.00

AC:

AN:

238

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53219

Other (OTH)

AF:

0.00

AC:

AN:

1501

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000217

Hom.:

Bravo

AF:

0.0000642

ExAC

AF:

0.0000742

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 26, 2021

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.88G>A (p.G30R) alteration is located in exon 1 (coding exon 1) of the PIN4 gene. This alteration results from a G to A substitution at nucleotide position 88, causing the glycine (G) at amino acid position 30 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

Pathogenic

0.64

BayesDel_addAF

Pathogenic

0.23

BayesDel_noAF

Uncertain

0.090

CADD

Uncertain

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.090

T;.;.;T

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.93

.;D;D;.

M_CAP

Benign

0.049

MetaRNN

Benign

0.057

T;T;T;T

MetaSVM

Benign

-0.38

PhyloP100

4.1

PrimateAI

Uncertain

0.65

PROVEAN

Benign

-1.3

N;N;N;N

REVEL

Benign

0.18

Sift

Uncertain

0.0030

D;D;D;D

Sift4G

Uncertain

0.033

D;D;T;D

Polyphen

0.99

.;.;D;.

Vest4

0.43

MutPred

0.26

Gain of solvent accessibility (P = 0.019);Gain of solvent accessibility (P = 0.019);Gain of solvent accessibility (P = 0.019);.;

MVP

0.51

MPC

0.57

ClinPred

0.43

GERP RS

5.2

PromoterAI

-0.015

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

gMVP

0.51

Mutation Taster

=55/45

polymorphism

(source)

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

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X-72181798-G-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over