NM_001018109.3:c.847A>T

Variant names:

• chrX-15385030-T-A
• rs200265489
• NM_001018109.3:c.847A>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001018109.3(PIR):​c.847A>T​(p.Thr283Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000111 in 1,167,587 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 6 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: 𝑓 0.000027 (0 hom., 1 hem., cov: 23)
  • Exomes 𝑓: 0.0000095 (0 hom. 5 hem.)
• Consequence: PIR NM_001018109.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.25
• 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.121379435).
• BS2: High Hemizygotes in GnomAdExome4 at 5 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIR	NM_001018109.3	c.847A>T	p.Thr283Ser	missense_variant	Exon 10 of 10	ENST00000380420.10	NP_001018119.1
PIR	NM_003662.4	c.847A>T	p.Thr283Ser	missense_variant	Exon 10 of 10		NP_003653.1
PIR-FIGF	NR_037859.2	n.1065+5155A>T		intron_variant	Intron 9 of 14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PIR	ENST00000380420.10	c.847A>T	p.Thr283Ser	missense_variant	Exon 10 of 10	1	NM_001018109.3	ENSP00000369785.5
PIR	ENST00000380421.3	c.847A>T	p.Thr283Ser	missense_variant	Exon 10 of 10	1		ENSP00000369786.3
PIR	ENST00000492432.5	n.385A>T		non_coding_transcript_exon_variant	Exon 4 of 4	2

Frequencies

GnomAD3 genomes AF: 0.0000268 AC: 3 AN: 112019 Hom.: 0 Cov.: 23

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: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000563

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000166 AC: 3 AN: 180565 AF XY: 0.0000307

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: 0.0000371

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000947 AC: 10 AN: 1055568 Hom.: 0 Cov.: 21 AF XY: 0.0000152 AC XY: 5 AN XY: 328382

African (AFR) AF: 0.00 AC: 0 AN: 25575

American (AMR) AF: 0.00 AC: 0 AN: 35002

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19107

East Asian (EAS) AF: 0.00 AC: 0 AN: 29909

South Asian (SAS) AF: 0.00 AC: 0 AN: 52956

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40319

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4032

European-Non Finnish (NFE) AF: 0.0000124 AC: 10 AN: 803936

Other (OTH) AF: 0.00 AC: 0 AN: 44732

GnomAD4 genome AF: 0.0000268 AC: 3 AN: 112019 Hom.: 0 Cov.: 23 AF XY: 0.0000293 AC XY: 1 AN XY: 34183

African (AFR) AF: 0.00 AC: 0 AN: 30800

American (AMR) AF: 0.00 AC: 0 AN: 10544

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2641

East Asian (EAS) AF: 0.00 AC: 0 AN: 3582

South Asian (SAS) AF: 0.00 AC: 0 AN: 2676

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6095

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 236

European-Non Finnish (NFE) AF: 0.0000563 AC: 3 AN: 53247

Other (OTH) AF: 0.00 AC: 0 AN: 1514

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000302

ExAC AF: 0.0000412 AC: 5

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 13, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.847A>T (p.T283S) alteration is located in exon 10 (coding exon 9) of the PIR gene. This alteration results from a A to T substitution at nucleotide position 847, causing the threonine (T) at amino acid position 283 to be replaced by a serine (S). 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	-0.35	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	13
DANN	Benign	0.96
DEOGEN2	Benign	0.044	T;T
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Uncertain	0.89	.;D
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.12	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.86	L;L
PhyloP100		1.3
PrimateAI	Benign	0.42	T
PROVEAN	Benign	0.57	N;N
REVEL	Benign	0.11
Sift	Benign	0.45	T;T
Sift4G	Benign	0.50	T;T
Polyphen		0.0	B;B
Vest4		0.12
MutPred		0.37		Gain of disorder (P = 0.0308);Gain of disorder (P = 0.0308);
MVP		0.52
MPC		0.023
ClinPred		0.072	T
GERP RS		5.1
Varity_R		0.14
gMVP		0.44
Mutation Taster		=100/0	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

dbSNP: rs200265489; hg19: chrX-15403152;