chrX-15456011-C-T

Variant names:

• chrX-15456011-C-T
• rs35715407
• NM_001018109.3:c.317G>A

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.317G>A​(p.Cys106Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.00000331 in 1,209,905 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. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C106F) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0000089 (0 hom., 0 hem., cov: 24)
  • Exomes 𝑓: 0.0000027 (0 hom. 2 hem.)
• Consequence: PIR NM_001018109.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.58
• Publications: 2 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=0.18730372).
• 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	c.317G>A	p.Cys106Tyr	missense_variant	Exon 5 of 10	ENST00000380420.10	NP_001018119.1
PIR	NM_003662.4	c.317G>A	p.Cys106Tyr	missense_variant	Exon 5 of 10		NP_003653.1
PIR-FIGF	NR_037859.2	n.369G>A		non_coding_transcript_exon_variant	Exon 4 of 15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PIR	ENST00000380420.10	c.317G>A	p.Cys106Tyr	missense_variant	Exon 5 of 10	1	NM_001018109.3	ENSP00000369785.5
PIR	ENST00000380421.3	c.317G>A	p.Cys106Tyr	missense_variant	Exon 5 of 10	1		ENSP00000369786.3
PIR	ENST00000476381.5	n.267G>A		non_coding_transcript_exon_variant	Exon 4 of 5	3

Frequencies

GnomAD3 genomes AF: 0.00000892 AC: 1 AN: 112141 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000279

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000546 AC: 1 AN: 183291 AF XY: 0.0000148

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000721

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000273 AC: 3 AN: 1097712 Hom.: 0 Cov.: 30 AF XY: 0.00000551 AC XY: 2 AN XY: 363098

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 26384

American (AMR) AF: 0.00 AC: 0 AN: 35207

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19381

East Asian (EAS) AF: 0.0000662 AC: 2 AN: 30206

South Asian (SAS) AF: 0.00 AC: 0 AN: 54135

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40478

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4058

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 841787

Other (OTH) AF: 0.0000217 AC: 1 AN: 46076

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00000891 AC: 1 AN: 112193 Hom.: 0 Cov.: 24 AF XY: 0.00 AC XY: 0 AN XY: 34365

African (AFR) AF: 0.00 AC: 0 AN: 30879

American (AMR) AF: 0.00 AC: 0 AN: 10617

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2654

East Asian (EAS) AF: 0.000280 AC: 1 AN: 3576

South Asian (SAS) AF: 0.00 AC: 0 AN: 2671

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6105

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 219

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53242

Other (OTH) AF: 0.00 AC: 0 AN: 1544

Alfa AF: 0.00 Hom.: 36

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	18
DANN	Benign	0.50
DEOGEN2	Benign	0.081	T;T
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.91	.;D
M_CAP	Uncertain	0.19	D
MetaRNN	Benign	0.19	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.90	N;N
PhyloP100		3.6
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-0.47	N;N
REVEL	Benign	0.076
Sift	Benign	0.78	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0070	B;B
Vest4		0.29
MutPred		0.34		Loss of catalytic residue at P105 (P = 0.0079);Loss of catalytic residue at P105 (P = 0.0079);
MVP		0.79
MPC		0.033
ClinPred		0.19	T
GERP RS		6.1
Varity_R		0.39
gMVP		0.80
Mutation Taster		=98/2	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: rs35715407; hg19: chrX-15474134;