Genetic Variant NM_006223.4:c.34G>C (chrX-72181819-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_006223.4(PIN4):c.34G>C(p.Ala12Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000966 in 1,035,181 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. 13/18 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. A12T) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 24)

Exomes 𝑓: 9.7e-7 ( 0 hom. 0 hem. )

Consequence

PIN4
NM_006223.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.54

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=0.11293253).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006223.4. 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.34G>C	p.Ala12Pro	missense	Exon 1 of 4	NP_006214.3
PIN4	NM_001170747.1		c.109G>C	p.Ala37Pro	missense	Exon 1 of 4	NP_001164218.1	Q9Y237-3
PIN4	NR_033187.2		n.63G>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.34G>C	p.Ala12Pro	missense	Exon 1 of 4	ENSP00000362773.3	Q9Y237-1
PIN4	ENST00000664196.1		c.109G>C	p.Ala37Pro	missense	Exon 1 of 4	ENSP00000499466.1	Q9Y237-2
PIN4	ENST00000423432.6	TSL:2	c.109G>C	p.Ala37Pro	missense	Exon 1 of 4	ENSP00000409154.2	Q9Y237-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

9.66e-7

AC:

AN:

1035181

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

309727

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

25553

American (AMR)

AF:

0.00

AC:

AN:

33798

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18868

East Asian (EAS)

AF:

0.00

AC:

AN:

29879

South Asian (SAS)

AF:

0.00

AC:

AN:

51546

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39941

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3822

European-Non Finnish (NFE)

AF:

0.00000127

AC:

AN:

787714

Other (OTH)

AF:

0.00

AC:

AN:

44060

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.40

CADD

Uncertain

(source)

DANN

Benign

0.88

DEOGEN2

Benign

0.064

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.34

M_CAP

Benign

0.028

MetaRNN

Benign

0.11

MetaSVM

Benign

-0.83

PhyloP100

2.5

PrimateAI

Benign

0.38

PROVEAN

Benign

-1.2

REVEL

Benign

0.063

Sift

Benign

0.074

Sift4G

Benign

0.096

Polyphen

0.12

Vest4

0.25

MutPred

0.18

Loss of MoRF binding (P = 0.0606)

MVP

0.27

MPC

0.17

ClinPred

0.30

GERP RS

4.2

PromoterAI

0.16

Neutral

(source)

gMVP

0.53

Mutation Taster

=75/25

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over