X-15456011-C-A

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_001018109.3(PIR):​c.317G>T​(p.Cys106Phe) variant causes a missense change. The variant allele was found at a frequency of 0.000595 in 1,209,905 control chromosomes in the GnomAD database, including 2 homozygotes. There are 189 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0028 (2 hom., 78 hem., cov: 24)
  • Exomes 𝑓: 0.00037 (0 hom. 111 hem.)
• Consequence: PIR NM_001018109.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• 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: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008328557).
• BP6: Variant X-15456011-C-A is Benign according to our data. Variant chrX-15456011-C-A is described in ClinVar as [Benign]. Clinvar id is 717759.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd4 at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIR	NM_001018109.3	c.317G>T	p.Cys106Phe	missense_variant	Exon 5 of 10	ENST00000380420.10	NP_001018119.1
PIR	NM_003662.4	c.317G>T	p.Cys106Phe	missense_variant	Exon 5 of 10		NP_003653.1
PIR-FIGF	NR_037859.2	n.369G>T		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>T	p.Cys106Phe	missense_variant	Exon 5 of 10	1	NM_001018109.3	ENSP00000369785.5
PIR	ENST00000380421.3	c.317G>T	p.Cys106Phe	missense_variant	Exon 5 of 10	1		ENSP00000369786.3
PIR	ENST00000476381.5	n.267G>T		non_coding_transcript_exon_variant	Exon 4 of 5	3

Frequencies

GnomAD3 genomes AF: 0.00278 AC: 312 AN: 112141 Hom.: 2 Cov.: 24

Gnomad AFR AF: 0.00996

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000189

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: 0.0000188

Gnomad OTH AF: 0.00131

GnomAD2 exomes AF: 0.000988 AC: 181 AN: 183291 AF XY: 0.000753

Gnomad AFR exome AF: 0.00927

Gnomad AMR exome AF: 0.00157

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000134

Gnomad OTH exome AF: 0.00110

GnomAD4 exome AF: 0.000371 AC: 407 AN: 1097712 Hom.: 0 Cov.: 30 AF XY: 0.000306 AC XY: 111 AN XY: 363098

African (AFR) AF: 0.00974 AC: 257 AN: 26384

American (AMR) AF: 0.00156 AC: 55 AN: 35207

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 30206

South Asian (SAS) AF: 0.0000369 AC: 2 AN: 54135

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

Middle Eastern (MID) AF: 0.00123 AC: 5 AN: 4058

European-Non Finnish (NFE) AF: 0.0000558 AC: 47 AN: 841787

Other (OTH) AF: 0.000890 AC: 41 AN: 46076

GnomAD4 genome AF: 0.00279 AC: 313 AN: 112193 Hom.: 2 Cov.: 24 AF XY: 0.00227 AC XY: 78 AN XY: 34365

African (AFR) AF: 0.00997 AC: 308 AN: 30879

American (AMR) AF: 0.000188 AC: 2 AN: 10617

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

East Asian (EAS) AF: 0.00 AC: 0 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: 0.0000188 AC: 1 AN: 53242

Other (OTH) AF: 0.00130 AC: 2 AN: 1544

Alfa AF: 0.000874 Hom.: 36

Bravo AF: 0.00336

ESP6500AA AF: 0.00913 AC: 35

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000955 AC: 116

EpiCase AF: 0.0000545

EpiControl AF: 0.000415

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jul 26, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	19
DANN	Benign	0.88
DEOGEN2	Benign	0.10	T;T
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.92	.;D
MetaRNN	Benign	0.0083	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.63	N;N
PhyloP100		3.6
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-0.91	N;N
REVEL	Benign	0.12
Sift	Benign	0.55	T;T
Sift4G	Benign	0.70	T;T
Polyphen		0.51	P;P
Vest4		0.29
MVP		0.75
MPC		0.058
ClinPred		0.012	T
GERP RS		6.1
Varity_R		0.52
gMVP		0.81
Mutation Taster		=99/1	polymorphism (auto)

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;