Genetic Variant ENST00000664196.1:c.7A>G (chrX-72181717-A-G) – ACMG Classification: Benign (-8 pts)

Variant summary

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

The ENST00000664196.1(PIN4):c.7A>G(p.Met3Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000712 in 982,699 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 4 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. 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. M3L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 24)

Exomes 𝑓: 0.0000071 ( 0 hom. 4 hem. )

Consequence

PIN4
ENST00000664196.1 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.20

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=0.04496005).

BS2

High Hemizygotes in GnomAdExome4 at 4 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIN4	NM_001170747.1 link	c.7A>G	p.Met3Val	missense_variant	Exon 1 of 4		NP_001164218.1	Q9Y237-3
PIN4	NM_006223.4 link	c.-69A>G		upstream_gene_variant		ENST00000373669.8	NP_006214.3	Q9Y237-1
PIN4	NR_033187.2 link	n.-40A>G		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PIN4	ENST00000373669.8 link	c.-69A>G		upstream_gene_variant		1	NM_006223.4	ENSP00000362773.3		Q9Y237-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000219

AC:

AN:

182767

AF XY:

0.0000446

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

AF:

0.00000712

AC:

AN:

982699

Hom.:

Cov.:

AF XY:

0.0000137

AC XY:

AN XY:

291311

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

25021

American (AMR)

AF:

0.00

AC:

AN:

35077

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18667

East Asian (EAS)

AF:

0.00

AC:

AN:

29962

South Asian (SAS)

AF:

0.000115

AC:

AN:

52163

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40481

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2732

European-Non Finnish (NFE)

AF:

0.00000136

AC:

AN:

736194

Other (OTH)

AF:

0.00

AC:

AN:

42402

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000247

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.67

BayesDel_noAF

Benign

-0.92

CADD

Benign

0.026

(source)

DANN

Benign

0.60

DEOGEN2

Benign

0.043

T;.;.

FATHMM_MKL

Benign

0.020

LIST_S2

Benign

0.30

.;T;T

M_CAP

Benign

0.0021

MetaRNN

Benign

0.045

T;T;T

MetaSVM

Benign

-0.96

PhyloP100

-1.2

PrimateAI

Benign

0.31

PROVEAN

Benign

0.070

N;N;N

REVEL

Benign

0.045

Sift

Pathogenic

0.0

D;D;D

Sift4G

Benign

0.49

T;T;T

Polyphen

0.0

.;.;B

Vest4

0.014

MutPred

0.22

Loss of ubiquitination at K8 (P = 0.0877);Loss of ubiquitination at K8 (P = 0.0877);Loss of ubiquitination at K8 (P = 0.0877);

MVP

0.093

MPC

0.11

ClinPred

0.049

GERP RS

-8.3

PromoterAI

-0.13

Neutral

(source)

gMVP

0.28

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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ENST00000664196.1:c.7A>G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over