Genetic Variant NM_006223.4:c.346G>A (chrX-72197476-G-A) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_006223.4(PIN4):c.346G>A(p.Val116Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000183 in 1,093,656 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 0.0000018 ( 0 hom. 2 hem. )

Consequence

PIN4
NM_006223.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.59

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: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.19652441).

BS2

High Hemizygotes in GnomAdExome4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIN4	NM_006223.4 link	c.346G>A	p.Val116Ile	missense_variant	Exon 4 of 4	ENST00000373669.8	NP_006214.3	Q9Y237-1
PIN4	NR_033187.2 link	n.301G>A		non_coding_transcript_exon_variant	Exon 3 of 3
PIN4	NM_001170747.1 link	c.312+572G>A		intron_variant	Intron 3 of 3		NP_001164218.1	Q9Y237-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PIN4	ENST00000373669.8 link	c.346G>A	p.Val116Ile	missense_variant	Exon 4 of 4	1	NM_006223.4	ENSP00000362773.3		Q9Y237-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000183

AC:

AN:

1093656

Hom.:

Cov.:

AF XY:

0.00000557

AC XY:

AN XY:

359130

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26342

American (AMR)

AF:

0.00

AC:

AN:

35134

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19332

East Asian (EAS)

AF:

0.00

AC:

AN:

30181

South Asian (SAS)

AF:

0.00

AC:

AN:

53857

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40506

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4117

European-Non Finnish (NFE)

AF:

0.00000119

AC:

AN:

838244

Other (OTH)

AF:

0.0000218

AC:

AN:

45943

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Sep 14, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.421G>A (p.V141I) alteration is located in exon 4 (coding exon 4) of the PIN4 gene. This alteration results from a G to A substitution at nucleotide position 421, causing the valine (V) at amino acid position 141 to be replaced by an isoleucine (I). 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

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.47

CADD

Benign

(source)

DANN

Benign

0.91

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.90

M_CAP

Benign

0.0048

MetaRNN

Benign

0.20

MetaSVM

Benign

-1.0

PhyloP100

4.6

PrimateAI

Benign

0.42

PROVEAN

Benign

-0.54

REVEL

Benign

0.086

Sift

Benign

0.16

Sift4G

Benign

0.20

Polyphen

0.068

Vest4

0.27

MutPred

0.76

Loss of disorder (P = 0.1587);

MVP

0.15

MPC

0.097

ClinPred

0.28

GERP RS

2.6

gMVP

0.43

Mutation Taster

=89/11

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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NM_006223.4:c.346G>A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over