NM_001018109.3:c.433G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001018109.3(PIR):c.433G>A(p.Asp145Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000198 in 1,209,455 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 13 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000089 ( 0 hom., 1 hem., cov: 23)

Exomes 𝑓: 0.000021 ( 0 hom. 12 hem. )

Consequence

PIR
NM_001018109.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.52

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: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.047415763).

BS2

High Hemizygotes in GnomAdExome4 at 12 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIR	NM_001018109.3 link	c.433G>A	p.Asp145Asn	missense_variant	Exon 5 of 10	ENST00000380420.10	NP_001018119.1	O00625A0A024RBX6
PIR	NM_003662.4 link	c.433G>A	p.Asp145Asn	missense_variant	Exon 5 of 10		NP_003653.1	O00625A0A024RBX6
PIR-FIGF	NR_037859.2 link	n.485G>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.433G>A	p.Asp145Asn	missense_variant	Exon 5 of 10	1	NM_001018109.3	ENSP00000369785.5	O00625
PIR	ENST00000380421.3 link	c.433G>A	p.Asp145Asn	missense_variant	Exon 5 of 10	1		ENSP00000369786.3	O00625
PIR	ENST00000476381.5 link	n.383G>A		non_coding_transcript_exon_variant	Exon 4 of 5	3

Frequencies

GnomAD3 genomes

AF:

0.00000891

AC:

AN:

112177

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000370

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000872

AC:

AN:

183464

AF XY:

0.000103

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:

0.0000210

AC:

AN:

1097278

Hom.:

Cov.:

AF XY:

0.0000331

AC XY:

AN XY:

362650

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26380

American (AMR)

AF:

0.00

AC:

AN:

35206

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19382

East Asian (EAS)

AF:

0.00

AC:

AN:

30201

South Asian (SAS)

AF:

0.000388

AC:

AN:

54125

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40534

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4136

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

841255

Other (OTH)

AF:

0.0000434

AC:

AN:

46059

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000891

AC:

AN:

112177

Hom.:

Cov.:

AF XY:

0.0000291

AC XY:

AN XY:

34327

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30799

American (AMR)

AF:

0.00

AC:

AN:

10651

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2647

East Asian (EAS)

AF:

0.00

AC:

AN:

3586

South Asian (SAS)

AF:

0.000370

AC:

AN:

2704

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6119

Middle Eastern (MID)

AF:

0.00

AC:

AN:

240

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53240

Other (OTH)

AF:

0.00

AC:

AN:

1505

Alfa

AF:

0.000223

Hom.:

ExAC

AF:

0.000115

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 05, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.433G>A (p.D145N) 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 433, causing the aspartic acid (D) at amino acid position 145 to be replaced by an asparagine (N). 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

0.090

BayesDel_addAF

Benign

-0.72

BayesDel_noAF

Benign

-0.89

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.32

T;T

FATHMM_MKL

Uncertain

0.77

LIST_S2

Benign

0.85

.;D

M_CAP

Uncertain

0.28

MetaRNN

Benign

0.047

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.4

L;L

PhyloP100

1.5

PrimateAI

Benign

0.33

PROVEAN

Uncertain

-4.1

D;D

REVEL

Benign

0.069

Sift

Benign

0.054

T;T

Sift4G

Uncertain

0.058

T;T

Polyphen

0.0

B;B

Vest4

0.026

MutPred

0.29

Loss of ubiquitination at K144 (P = 0.0613);Loss of ubiquitination at K144 (P = 0.0613);

MVP

0.41

MPC

0.024

ClinPred

0.080

GERP RS

2.7

Varity_R

0.39

gMVP

0.45

Mutation Taster

=98/2

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.433G>A

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