rs17089782
Positions:
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
NM_006346.4 missense
Scores
6
6
6
Clinical Significance
Conservation
PhyloP100: 8.93
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]
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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 | c.1214G>A | p.Arg405Gln | missense_variant | 9/18 | ENST00000326291.11 | NP_006337.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
PIBF1 | ENST00000326291.11 | c.1214G>A | p.Arg405Gln | missense_variant | 9/18 | 1 | NM_006346.4 | ENSP00000317144.6 | ||
PIBF1 | ENST00000617689.4 | c.1214G>A | p.Arg405Gln | missense_variant | 9/16 | 1 | ENSP00000478697.1 | |||
PIBF1 | ENST00000615625 | c.-145G>A | 5_prime_UTR_variant | 2/9 | 1 | ENSP00000483286.1 |
Frequencies
GnomAD3 genomes AF: 0.00833 AC: 1204AN: 144558Hom.: 34 Cov.: 32
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GnomAD3 exomes AF: 0.0148 AC: 2871AN: 194276Hom.: 132 AF XY: 0.0120 AC XY: 1280AN XY: 106866
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GnomAD4 exome AF: 0.00369 AC: 5193AN: 1406408Hom.: 183 Cov.: 29 AF XY: 0.00348 AC XY: 2435AN XY: 699384
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GnomAD4 genome AF: 0.00832 AC: 1203AN: 144666Hom.: 33 Cov.: 32 AF XY: 0.00933 AC XY: 657AN XY: 70402
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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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Benign
T;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D
MetaRNN
Benign
T;T
MetaSVM
Benign
T
MutationAssessor
Uncertain
M;.
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;.
REVEL
Uncertain
Sift
Pathogenic
D;.
Sift4G
Uncertain
D;D
Polyphen
D;.
Vest4
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at