chrX-15425959-T-C

Variant names:

• chrX-15425959-T-C
• NM_001018109.3:c.512A>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001018109.3(PIR):​c.512A>G​(p.Tyr171Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 22)
• Consequence: PIR NM_001018109.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.78
• Publications: 0 publications found

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-FIGF (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.922

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIR	NM_001018109.3	c.512A>G	p.Tyr171Cys	missense_variant	Exon 6 of 10	ENST00000380420.10	NP_001018119.1
PIR	NM_003662.4	c.512A>G	p.Tyr171Cys	missense_variant	Exon 6 of 10		NP_003653.1
PIR-FIGF	NR_037859.2	n.564A>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	c.512A>G	p.Tyr171Cys	missense_variant	Exon 6 of 10	1	NM_001018109.3	ENSP00000369785.5
PIR	ENST00000380421.3	c.512A>G	p.Tyr171Cys	missense_variant	Exon 6 of 10	1		ENSP00000369786.3

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 25

GnomAD4 genome Cov.: 22

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 13, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.512A>G (p.Y171C) 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 512, causing the tyrosine (Y) at amino acid position 171 to be replaced by a cysteine (C). 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	Pathogenic	0.68
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.16
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.44	T;T
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Pathogenic	0.99	.;D
M_CAP	Uncertain	0.29	D
MetaRNN	Pathogenic	0.92	D;D
MetaSVM	Benign	-0.55	T
MutationAssessor	Pathogenic	3.3	M;M
PhyloP100		2.8
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-8.1	D;D
REVEL	Uncertain	0.37
Sift	Benign	0.046	D;D
Sift4G	Uncertain	0.060	T;T
Polyphen		0.76	P;P
Vest4		0.88
MutPred		0.75		Gain of catalytic residue at L172 (P = 0.0107);Gain of catalytic residue at L172 (P = 0.0107);
MVP		0.89
MPC		0.21
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.99
gMVP		0.89
Mutation Taster		=62/38	polymorphism

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

Other links and lift over

hg19: chrX-15444082;