Genetic Variant PIN4:p.Arg12Gly (chrX-72181744-C-G) – ACMG Classification: Benign (-8 pts)

Variant summary

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

The NM_001170747.1(PIN4):c.34C>G(p.Arg12Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000011 in 1,179,772 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 6 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000063 ( 0 hom., 2 hem., cov: 24)

Exomes 𝑓: 0.0000056 ( 0 hom. 4 hem. )

Consequence

PIN4
NM_001170747.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.82

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=0.0476636).

BS2

High Hemizygotes in GnomAd4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIN4	NM_001170747.1 link	c.34C>G	p.Arg12Gly	missense_variant	Exon 1 of 4		NP_001164218.1	Q9Y237-3
PIN4	NM_006223.4 link	c.-42C>G		upstream_gene_variant		ENST00000373669.8	NP_006214.3	Q9Y237-1
PIN4	NR_033187.2 link	n.-13C>G		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PIN4	ENST00000373669.8 link	c.-42C>G		upstream_gene_variant		1	NM_006223.4	ENSP00000362773.3		Q9Y237-1

Frequencies

GnomAD3 genomes

AF:

0.0000625

AC:

AN:

111947

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000228

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000219

AC:

AN:

182846

AF XY:

0.0000148

show subpopulations

Gnomad AFR exome

AF:

0.000305

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000562

AC:

AN:

1067825

Hom.:

Cov.:

AF XY:

0.0000118

AC XY:

AN XY:

339325

show subpopulations

African (AFR)

AF:

0.000231

AC:

AN:

26028

American (AMR)

AF:

0.00

AC:

AN:

35168

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19200

East Asian (EAS)

AF:

0.00

AC:

AN:

30161

South Asian (SAS)

AF:

0.00

AC:

AN:

53560

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40511

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3042

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

815043

Other (OTH)

AF:

0.00

AC:

AN:

45112

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:

0.0000625

AC:

AN:

111947

Hom.:

Cov.:

AF XY:

0.0000586

AC XY:

AN XY:

34121

show subpopulations

African (AFR)

AF:

0.000228

AC:

AN:

30758

American (AMR)

AF:

0.00

AC:

AN:

10590

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2652

East Asian (EAS)

AF:

0.00

AC:

AN:

3570

South Asian (SAS)

AF:

0.00

AC:

AN:

2742

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6018

Middle Eastern (MID)

AF:

0.00

AC:

AN:

237

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53187

Other (OTH)

AF:

0.00

AC:

AN:

1509

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.555

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000567

ESP6500AA

AF:

0.000522

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Sep 17, 2021

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.34C>G (p.R12G) alteration is located in exon 1 (coding exon 1) of the PIN4 gene. This alteration results from a C to G substitution at nucleotide position 34, causing the arginine (R) at amino acid position 12 to be replaced by a glycine (G). 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

BayesDel_addAF

Benign

-0.70

BayesDel_noAF

Benign

-0.94

CADD

Benign

0.25

(source)

DANN

Benign

0.48

DEOGEN2

Benign

0.043

T;.;.

FATHMM_MKL

Benign

0.16

LIST_S2

Benign

0.53

.;T;T

M_CAP

Benign

0.0083

MetaRNN

Benign

0.048

T;T;T

MetaSVM

Benign

-1.0

PhyloP100

-1.8

PrimateAI

Benign

0.27

PROVEAN

Benign

0.050

N;N;N

REVEL

Benign

0.0080

Sift

Uncertain

0.0030

D;D;D

Sift4G

Uncertain

0.011

D;D;D

Polyphen

0.0

.;.;B

Vest4

0.12

MVP

0.043

MPC

0.14

ClinPred

0.019

GERP RS

-4.9

PromoterAI

-0.22

Neutral

(source)

gMVP

0.36

Mutation Taster

=100/0

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-72181744-C-G

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