rs17089782

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_006346.4(PIBF1):c.1214G>A(p.Arg405Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00412 in 1,551,074 control chromosomes in the GnomAD database, including 216 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0083 ( 33 hom., cov: 32)

Exomes 𝑓: 0.0037 ( 183 hom. )

Consequence

PIBF1
NM_006346.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:4B:3

Conservation

PhyloP100: 8.93

Publications

13 publications found

Variant links:

Genes affected

PIBF1 (HGNC:23352): (progesterone immunomodulatory binding factor 1) This gene encodes a protein that is induced by the steroid hormone progesterone and plays a role in the maintenance of pregnancy. The encoded protein regulates multiple facets of the immune system to promote normal pregnancy including cytokine synthesis, natural killer (NK) cell activity, and arachidonic acid metabolism. Low serum levels of this protein have been associated with spontaneous pre-term labor in humans. This protein may promote the proliferation, migration and invasion of glioma. [provided by RefSeq, Mar 2017]

PIBF1 Gene-Disease associations (from GenCC):

Joubert syndrome 33
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
ciliopathy
Inheritance: AR Classification: MODERATE Submitted by: ClinGen
Joubert syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

PIBF1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.005607307).

BP6

Variant 13-72835359-G-A is Benign according to our data. Variant chr13-72835359-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 217689.We mark this variant Likely_benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00832 (1203/144666) while in subpopulation EAS AF = 0.0545 (268/4920). AF 95% confidence interval is 0.0504. There are 33 homozygotes in GnomAd4. There are 657 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 33 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIBF1	NM_006346.4 link	c.1214G>A	p.Arg405Gln	missense_variant	Exon 9 of 18	ENST00000326291.11	NP_006337.2	Q8WXW3-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PIBF1	ENST00000326291.11 link	c.1214G>A	p.Arg405Gln	missense_variant	Exon 9 of 18	1	NM_006346.4	ENSP00000317144.6	Q8WXW3-1
PIBF1	ENST00000617689.4 link	c.1214G>A	p.Arg405Gln	missense_variant	Exon 9 of 16	1		ENSP00000478697.1	A0A087WUI6
PIBF1	ENST00000615625.1 link	c.-145G>A		5_prime_UTR_variant	Exon 2 of 9	1		ENSP00000483286.1	Q8WXW3-2
PIBF1	ENST00000492803.1 link	n.*83G>A		downstream_gene_variant		3

Frequencies

GnomAD3 genomes

AF:

0.00833

AC:

1204

AN:

144558

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00196

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0535

Gnomad ASJ

AF:

0.000299

Gnomad EAS

AF:

0.0546

Gnomad SAS

AF:

0.00600

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000333

Gnomad OTH

AF:

0.0122

GnomAD2 exomes

AF:

0.0148

AC:

2871

AN:

194276

AF XY:

0.0120

show subpopulations

Gnomad AFR exome

AF:

0.00151

Gnomad AMR exome

AF:

0.103

Gnomad ASJ exome

AF:

0.000847

Gnomad EAS exome

AF:

0.0509

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000220

Gnomad OTH exome

AF:

0.0115

GnomAD4 exome

AF:

0.00369

AC:

5193

AN:

1406408

Hom.:

183

Cov.:

AF XY:

0.00348

AC XY:

2435

AN XY:

699384

show subpopulations

African (AFR)

AF:

0.000705

AC:

AN:

29794

American (AMR)

AF:

0.0882

AC:

2758

AN:

31266

Ashkenazi Jewish (ASJ)

AF:

0.000628

AC:

AN:

23888

East Asian (EAS)

AF:

0.0433

AC:

1630

AN:

37636

South Asian (SAS)

AF:

0.00409

AC:

313

AN:

76598

European-Finnish (FIN)

AF:

0.0000574

AC:

AN:

52288

Middle Eastern (MID)

AF:

0.000364

AC:

AN:

5494

European-Non Finnish (NFE)

AF:

0.000125

AC:

136

AN:

1091692

Other (OTH)

AF:

0.00545

AC:

315

AN:

57752

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

212

425

637

850

1062

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00832

AC:

1203

AN:

144666

Hom.:

Cov.:

AF XY:

0.00933

AC XY:

657

AN XY:

70402

show subpopulations

African (AFR)

AF:

0.00195

AC:

AN:

38882

American (AMR)

AF:

0.0535

AC:

785

AN:

14684

Ashkenazi Jewish (ASJ)

AF:

0.000299

AC:

AN:

3346

East Asian (EAS)

AF:

0.0545

AC:

268

AN:

4920

South Asian (SAS)

AF:

0.00601

AC:

AN:

4492

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9160

Middle Eastern (MID)

AF:

0.00

AC:

AN:

286

European-Non Finnish (NFE)

AF:

0.000333

AC:

AN:

66002

Other (OTH)

AF:

0.0120

AC:

AN:

1994

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.510

Heterozygous variant carriers

109

164

218

273

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00401

Hom.:

Bravo

AF:

0.0130

ESP6500AA

AF:

0.00204

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.0141

AC:

1709

Asia WGS

AF:

0.0310

AC:

106

AN:

3456

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:4Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Joubert syndrome 33

Pathogenic:1Uncertain:2Benign:1

Aug 01, 2015

OMIM

Significance:Pathogenic

Review Status:flagged submission

Collection Method:literature only

- -

Jan 27, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:research

- -

Feb 17, 2022

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ACMG classification criteria: PM3 moderate, BS2 -

Jul 09, 2021

Center of Genomic medicine, Geneva, University Hospital of Geneva

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant found in trans with a nonsense mutation in an individual with Joubert syndrome. -

Joubert syndrome

Pathogenic:1Uncertain:1

Jan 06, 2020

Reproductive Health Research and Development, BGI Genomics

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:curation

NM_006346.2:c.1214G>A in the PIBF1 gene has an allele frequency of 0.102 in Latino subpopulation in the gnomAD database. Wheway et al reported a pedigree of family with compound heterozygous PIBF1 variants c.1214G>A p.Arg405Gln and a genomic deletion encompassing exons 6 to 9 (c.673-?_1322+?del) of PIBF1 in affected two individuals II.5 and II.7, with phase unknown (PMID: 26167768). It was reported that this variant should be excluded from BA1 rule and has been classified as VUS according to ClinGen Sequence Variant Interpretation Working Group (PMID: 30311383). ACMG/AMP criteria applied: PM3; BS2. -

Jul 13, 2015

UW Hindbrain Malformation Research Program, University of Washington

Significance:Likely pathogenic

Review Status:flagged submission

Collection Method:research

- -

not specified

Uncertain:1Benign:1

May 03, 2020

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 04, 2022

Mendelics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.33

BayesDel_addAF

Benign

-0.10

BayesDel_noAF

Pathogenic

0.16

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.31

T;.

Eigen

Pathogenic

0.80

Eigen_PC

Pathogenic

0.76

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.97

D;D

MetaRNN

Benign

0.0056

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.6

M;.

PhyloP100

8.9

PrimateAI

Uncertain

0.62

PROVEAN

Uncertain

-3.4

D;.

REVEL

Uncertain

0.41

Sift

Pathogenic

0.0

D;.

Sift4G

Uncertain

0.029

D;D

Polyphen

1.0

D;.

Vest4

0.55

MPC

0.34

ClinPred

0.035

GERP RS

5.1

Varity_R

0.82

gMVP

0.59

Mutation Taster

=77/23

disease causing (ClinVar)

(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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rs17089782

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