NM_001018109.3:c.556A>G

Variant names:

Variant summary

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

The NM_001018109.3(PIR):c.556A>G(p.Ile186Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000387 in 1,034,839 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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 22)

Exomes 𝑓: 0.0000039 ( 0 hom. 2 hem. )

Consequence

PIR
NM_001018109.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.326

Publications

0 publications found

Variant links:

Genes affected

PIR (HGNC:30048): (pirin) This gene encodes a member of the cupin superfamily. The encoded protein is an Fe(II)-containing nuclear protein expressed in all tissues of the body and concentrated within dot-like subnuclear structures. Interactions with nuclear factor I/CCAAT box transcription factor as well as B cell lymphoma 3-encoded oncoprotein suggest the encoded protein may act as a transcriptional cofactor and be involved in the regulation of DNA transcription and replication. Alternatively spliced transcript variants have been described. [provided by RefSeq, Jul 2008]

PIR Gene-Disease associations (from GenCC):

complex neurodevelopmental disorder
Inheritance: XL Classification: LIMITED Submitted by: Ambry Genetics

PIR links:

PIR-FIGF (HGNC:):

PIR-FIGF links:

Genome browser will be placed here

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=0.07270223).

BS2

High Hemizygotes in GnomAdExome4 at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIR	NM_001018109.3 link	c.556A>G	p.Ile186Val	missense_variant	Exon 6 of 10	ENST00000380420.10	NP_001018119.1	O00625A0A024RBX6
PIR	NM_003662.4 link	c.556A>G	p.Ile186Val	missense_variant	Exon 6 of 10		NP_003653.1	O00625A0A024RBX6
PIR-FIGF	NR_037859.2 link	n.608A>G		non_coding_transcript_exon_variant	Exon 5 of 15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PIR	ENST00000380420.10 link	c.556A>G	p.Ile186Val	missense_variant	Exon 6 of 10	1	NM_001018109.3	ENSP00000369785.5		O00625
PIR	ENST00000380421.3 link	c.556A>G	p.Ile186Val	missense_variant	Exon 6 of 10	1		ENSP00000369786.3		O00625

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000547

AC:

AN:

182667

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

AF:

0.00000387

AC:

AN:

1034839

Hom.:

Cov.:

AF XY:

0.00000636

AC XY:

AN XY:

314497

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

25155

American (AMR)

AF:

0.00

AC:

AN:

35132

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19003

East Asian (EAS)

AF:

0.00

AC:

AN:

29945

South Asian (SAS)

AF:

0.0000760

AC:

AN:

52601

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40488

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3962

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

784495

Other (OTH)

AF:

0.00

AC:

AN:

44058

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 29, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.556A>G (p.I186V) alteration is located in exon 6 (coding exon 5) of the PIR gene. This alteration results from a A to G substitution at nucleotide position 556, causing the isoleucine (I) at amino acid position 186 to be replaced by a valine (V). 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

0.070

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.75

CADD

Benign

7.2

(source)

DANN

Benign

0.74

DEOGEN2

Benign

0.043

T;T

FATHMM_MKL

Benign

0.56

LIST_S2

Benign

0.82

.;T

M_CAP

Benign

0.0067

MetaRNN

Benign

0.073

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.23

N;N

PhyloP100

0.33

PrimateAI

Benign

0.39

PROVEAN

Benign

-0.21

N;N

REVEL

Benign

0.068

Sift

Benign

0.62

T;T

Sift4G

Benign

0.74

T;T

Polyphen

0.016

B;B

Vest4

0.086

MutPred

0.49

Gain of ubiquitination at K181 (P = 0.1446);Gain of ubiquitination at K181 (P = 0.1446);

MVP

0.75

MPC

0.023

ClinPred

0.065

GERP RS

3.1

Varity_R

0.13

gMVP

0.20

Mutation Taster

=99/1

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_001018109.3:c.556A>G

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