Genetic Variant PIN4:p.Met3Thr (chrX-72181718-T-C) – 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.8T>C(p.Met3Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000237 in 1,098,458 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 9 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 (★). 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: 𝑓 0.000080 ( 0 hom., 5 hem., cov: 24)

Exomes 𝑓: 0.000017 ( 0 hom. 4 hem. )

Consequence

PIN4
NM_001170747.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.108

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=0.06578979).

BS2

High Hemizygotes in GnomAd4 at 5 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIN4	NM_001170747.1 link	c.8T>C	p.Met3Thr	missense_variant	Exon 1 of 4		NP_001164218.1	Q9Y237-3
PIN4	NM_006223.4 link	c.-68T>C		upstream_gene_variant		ENST00000373669.8	NP_006214.3	Q9Y237-1
PIN4	NR_033187.2 link	n.-39T>C		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PIN4	ENST00000373669.8 link	c.-68T>C		upstream_gene_variant		1	NM_006223.4	ENSP00000362773.3		Q9Y237-1

Frequencies

GnomAD3 genomes

AF:

0.0000801

AC:

AN:

112411

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000227

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000939

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:

0.000661

GnomAD2 exomes

AF:

0.0000219

AC:

AN:

182797

AF XY:

0.0000149

show subpopulations

Gnomad AFR exome

AF:

0.000152

Gnomad AMR exome

AF:

0.0000366

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:

0.000222

GnomAD4 exome

AF:

0.0000172

AC:

AN:

986047

Hom.:

Cov.:

AF XY:

0.0000137

AC XY:

AN XY:

292271

show subpopulations

African (AFR)

AF:

0.000399

AC:

AN:

25068

American (AMR)

AF:

0.0000285

AC:

AN:

35081

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18685

East Asian (EAS)

AF:

0.00

AC:

AN:

29967

South Asian (SAS)

AF:

0.00

AC:

AN:

52214

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40485

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2729

European-Non Finnish (NFE)

AF:

0.00000271

AC:

AN:

739325

Other (OTH)

AF:

0.0000941

AC:

AN:

42493

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.452

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000801

AC:

AN:

112411

Hom.:

Cov.:

AF XY:

0.000145

AC XY:

AN XY:

34553

show subpopulations

African (AFR)

AF:

0.000227

AC:

AN:

30892

American (AMR)

AF:

0.0000939

AC:

AN:

10646

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2660

East Asian (EAS)

AF:

0.00

AC:

AN:

3592

South Asian (SAS)

AF:

0.00

AC:

AN:

2766

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6090

Middle Eastern (MID)

AF:

0.00

AC:

AN:

238

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53326

Other (OTH)

AF:

0.000661

AC:

AN:

1514

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.550

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000356

Hom.:

Bravo

AF:

0.000125

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 15, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.8T>C (p.M3T) alteration is located in exon 1 (coding exon 1) of the PIN4 gene. This alteration results from a T to C substitution at nucleotide position 8, causing the methionine (M) at amino acid position 3 to be replaced by a threonine (T). 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

-0.62

BayesDel_noAF

Benign

-0.86

CADD

Benign

4.9

(source)

DANN

Benign

0.71

DEOGEN2

Benign

0.043

T;.;.

FATHMM_MKL

Benign

0.14

LIST_S2

Benign

0.24

.;T;T

M_CAP

Benign

0.0040

MetaRNN

Benign

0.066

T;T;T

MetaSVM

Benign

-1.0

PhyloP100

-0.11

PrimateAI

Benign

0.38

PROVEAN

Benign

0.080

N;N;N

REVEL

Benign

0.049

Sift

Pathogenic

0.0

D;D;D

Sift4G

Uncertain

0.038

D;D;T

Polyphen

0.0

.;.;B

Vest4

0.11

MVP

0.043

MPC

0.12

ClinPred

0.024

GERP RS

1.0

PromoterAI

-0.16

Neutral

(source)

gMVP

0.29

Mutation Taster

=94/6

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-72181718-T-C

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