rs201144539

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4BS2

The NM_001018109.3(PIR):c.290G>A(p.Arg97Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000207 in 1,208,382 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. 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. R97W) has been classified as Benign.

Frequency

Genomes: 𝑓 0.000036 ( 0 hom., 3 hem., cov: 23)

Exomes 𝑓: 0.000019 ( 0 hom. 6 hem. )

Consequence

PIR
NM_001018109.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.92

Publications

1 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 -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.36689538).

BS2

High Hemizygotes in GnomAd4 at 3 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIR	NM_001018109.3 link	c.290G>A	p.Arg97Gln	missense_variant	Exon 5 of 10	ENST00000380420.10	NP_001018119.1	O00625A0A024RBX6
PIR	NM_003662.4 link	c.290G>A	p.Arg97Gln	missense_variant	Exon 5 of 10		NP_003653.1	O00625A0A024RBX6
PIR-FIGF	NR_037859.2 link	n.342G>A		non_coding_transcript_exon_variant	Exon 4 of 15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PIR	ENST00000380420.10 link	c.290G>A	p.Arg97Gln	missense_variant	Exon 5 of 10	1	NM_001018109.3	ENSP00000369785.5	O00625
PIR	ENST00000380421.3 link	c.290G>A	p.Arg97Gln	missense_variant	Exon 5 of 10	1		ENSP00000369786.3	O00625
PIR	ENST00000476381.5 link	n.240G>A		non_coding_transcript_exon_variant	Exon 4 of 5	3

Frequencies

GnomAD3 genomes

AF:

0.0000357

AC:

AN:

112139

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000324

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000942

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:

0.0000376

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000109

AC:

AN:

182897

AF XY:

0.0000148

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:

0.0000122

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000192

AC:

AN:

1096190

Hom.:

Cov.:

AF XY:

0.0000166

AC XY:

AN XY:

361720

show subpopulations

African (AFR)

AF:

0.0000379

AC:

AN:

26370

American (AMR)

AF:

0.00

AC:

AN:

35207

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19373

East Asian (EAS)

AF:

0.00

AC:

AN:

30200

South Asian (SAS)

AF:

0.0000370

AC:

AN:

54098

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40289

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3843

European-Non Finnish (NFE)

AF:

0.0000190

AC:

AN:

840804

Other (OTH)

AF:

0.0000435

AC:

AN:

46006

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.445

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000357

AC:

AN:

112192

Hom.:

Cov.:

AF XY:

0.0000873

AC XY:

AN XY:

34368

show subpopulations

African (AFR)

AF:

0.0000324

AC:

AN:

30887

American (AMR)

AF:

0.0000941

AC:

AN:

10628

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2652

East Asian (EAS)

AF:

0.00

AC:

AN:

3576

South Asian (SAS)

AF:

0.00

AC:

AN:

2681

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6101

Middle Eastern (MID)

AF:

0.00

AC:

AN:

219

European-Non Finnish (NFE)

AF:

0.0000376

AC:

AN:

53230

Other (OTH)

AF:

0.00

AC:

AN:

1534

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000214

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 09, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.290G>A (p.R97Q) alteration is located in exon 5 (coding exon 4) of the PIR gene. This alteration results from a G to A substitution at nucleotide position 290, causing the arginine (R) at amino acid position 97 to be replaced by a glutamine (Q). 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

0.16

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.57

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.45

T;T

FATHMM_MKL

Uncertain

0.87

LIST_S2

Uncertain

0.95

.;D

M_CAP

Uncertain

0.24

MetaRNN

Benign

0.37

T;T

MetaSVM

Benign

-0.93

MutationAssessor

Pathogenic

3.4

M;M

PhyloP100

2.9

PrimateAI

Benign

0.33

PROVEAN

Uncertain

-3.6

D;D

REVEL

Benign

0.16

Sift

Uncertain

0.010

D;D

Sift4G

Uncertain

0.027

D;D

Polyphen

0.15

B;B

Vest4

0.075

MVP

0.53

MPC

0.028

ClinPred

0.86

GERP RS

4.3

Varity_R

0.65

gMVP

0.70

Mutation Taster

=95/5

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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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rs201144539

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