rs17089782

Positions:

chr13-72835359-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2

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:2

Conservation

PhyloP100: 8.93

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 links:

PIBF1 (HGNC:):

PIBF1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

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

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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAd4 at 33 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PIBF1	NM_006346.4 linkuse as main transcript	c.1214G>A	p.Arg405Gln	missense_variant	9/18	ENST00000326291.11	NP_006337.2	Q8WXW3-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
PIBF1	ENST00000326291.11 linkuse as main transcript	c.1214G>A	p.Arg405Gln	missense_variant	9/18	1	NM_006346.4	ENSP00000317144.6	Q8WXW3-1
PIBF1	ENST00000617689.4 linkuse as main transcript	c.1214G>A	p.Arg405Gln	missense_variant	9/16	1		ENSP00000478697.1	A0A087WUI6
PIBF1	ENST00000615625 linkuse as main transcript	c.-145G>A		5_prime_UTR_variant	2/9	1		ENSP00000483286.1	Q8WXW3-2

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

GnomAD3 exomes

AF:

0.0148

AC:

2871

AN:

194276

Hom.:

132

AF XY:

0.0120

AC XY:

1280

AN XY:

106866

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 SAS exome

AF:

0.00348

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

Gnomad4 AFR exome

AF:

0.000705

Gnomad4 AMR exome

AF:

0.0882

Gnomad4 ASJ exome

AF:

0.000628

Gnomad4 EAS exome

AF:

0.0433

Gnomad4 SAS exome

AF:

0.00409

Gnomad4 FIN exome

AF:

0.0000574

Gnomad4 NFE exome

AF:

0.000125

Gnomad4 OTH exome

AF:

0.00545

GnomAD4 genome

AF:

0.00832

AC:

1203

AN:

144666

Hom.:

Cov.:

AF XY:

0.00933

AC XY:

657

AN XY:

70402

show subpopulations

Gnomad4 AFR

AF:

0.00195

Gnomad4 AMR

AF:

0.0535

Gnomad4 ASJ

AF:

0.000299

Gnomad4 EAS

AF:

0.0545

Gnomad4 SAS

AF:

0.00601

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000333

Gnomad4 OTH

AF:

0.0120

Alfa

AF:

0.00284

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:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Joubert syndrome 33

Pathogenic:1Uncertain:2

Pathogenic, flagged submission	literature only	OMIM	Aug 01, 2015	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Center of Genomic medicine, Geneva, University Hospital of Geneva	Jul 09, 2021	Variant found in trans with a nonsense mutation in an individual with Joubert syndrome. -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Feb 17, 2022	ACMG classification criteria: PM3 moderate, BS2 -

Familial aplasia of the vermis

Pathogenic:1Uncertain:1

Likely pathogenic, flagged submission	research	UW Hindbrain Malformation Research Program, University of Washington	Jul 13, 2015	- -
Uncertain significance, no assertion criteria provided	curation	Reproductive Health Research and Development, BGI Genomics	Jan 06, 2020	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. -

not specified

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	May 03, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 22, 2024

- -

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

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;.

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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over