Genetic Variant PIN4:c.-21G>C (chrX-72181765-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_001170747.1(PIN4):c.55G>C(p.Val19Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000893 in 112,006 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. 14/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000089 ( 0 hom., 0 hem., cov: 23)

Exomes 𝑓: 0.0000028 ( 0 hom. 0 hem. )

Failed GnomAD Quality Control

Consequence

PIN4
NM_001170747.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.734

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: 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=0.16732708).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001170747.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PIN4	NM_006223.4	MANE Select	c.-21G>C		5_prime_UTR	Exon 1 of 4	NP_006214.3
PIN4	NM_001170747.1		c.55G>C	p.Val19Leu	missense	Exon 1 of 4	NP_001164218.1	Q9Y237-3
PIN4	NR_033187.2		n.9G>C		non_coding_transcript_exon	Exon 1 of 3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PIN4	ENST00000373669.8	TSL:1 MANE Select	c.-21G>C		5_prime_UTR	Exon 1 of 4	ENSP00000362773.3	Q9Y237-1
PIN4	ENST00000664196.1		c.55G>C	p.Val19Leu	missense	Exon 1 of 4	ENSP00000499466.1	Q9Y237-2
PIN4	ENST00000423432.6	TSL:2	c.55G>C	p.Val19Leu	missense	Exon 1 of 4	ENSP00000409154.2	Q9Y237-3

Frequencies

GnomAD3 genomes

AF:

0.00000893

AC:

AN:

112006

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000280

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:

0.00000548

AC:

AN:

182439

AF XY:

0.00

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000276

AC:

AN:

1085604

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

352736

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26232

American (AMR)

AF:

0.00

AC:

AN:

35175

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19308

East Asian (EAS)

AF:

0.0000331

AC:

AN:

30182

South Asian (SAS)

AF:

0.0000186

AC:

AN:

53789

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40514

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3359

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

831411

Other (OTH)

AF:

0.0000219

AC:

AN:

45634

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000893

AC:

AN:

112006

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34170

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30746

American (AMR)

AF:

0.00

AC:

AN:

10578

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2654

East Asian (EAS)

AF:

0.000280

AC:

AN:

3571

South Asian (SAS)

AF:

0.00

AC:

AN:

2734

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6089

Middle Eastern (MID)

AF:

0.00

AC:

AN:

240

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53202

Other (OTH)

AF:

0.00

AC:

AN:

1505

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.675

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.63

CADD

Benign

7.3

(source)

DANN

Benign

0.89

DEOGEN2

Benign

0.055

FATHMM_MKL

Benign

0.47

LIST_S2

Benign

0.57

M_CAP

Benign

0.026

MetaRNN

Benign

0.094

MetaSVM

Benign

-0.99

PhyloP100

0.73

PrimateAI

Benign

0.43

PROVEAN

Benign

-0.23

REVEL

Benign

0.019

Sift

Uncertain

0.0090

Sift4G

Benign

0.094

Polyphen

0.064

Vest4

0.26

MutPred

0.24

Loss of catalytic residue at V19 (P = 0.1143)

MVP

0.23

MPC

0.11

ClinPred

0.38

GERP RS

3.1

PromoterAI

-0.0035

Neutral

(source)

gMVP

0.22

Mutation Taster

=98/2

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over