rs17089782

chr13-72835359-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:4 B:2
• 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]

ACMG classification

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 GnomAd at 34 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PIBF1	NM_006346.4	c.1214G>A	p.Arg405Gln	missense_variant	9/18	ENST00000326291.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PIBF1	ENST00000326291.11	c.1214G>A	p.Arg405Gln	missense_variant	9/18	1	NM_006346.4	P1
PIBF1	ENST00000617689.4	c.1214G>A	p.Arg405Gln	missense_variant	9/16	1
PIBF1	ENST00000615625.1	c.-145G>A		5_prime_UTR_variant	2/9	1

Frequencies

GnomAD3 genomes AF: 0.00833 AC: 1204 AN: 144558 Hom.: 34 Cov.: 32

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

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.: 29 AF XY: 0.00348 AC XY: 2435 AN XY: 699384

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.: 33 Cov.: 32 AF XY: 0.00933 AC XY: 657 AN XY: 70402

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.: 19

Bravo AF: 0.0130

ESP6500AA AF: 0.00204 AC: 9

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.0141 AC: 1709

Asia WGS AF: 0.0310 AC: 106 AN: 3456

ClinVar

Significance: Conflicting classifications of pathogenicity

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

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Joubert syndrome 33 Pathogenic:1 Uncertain:2

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 -
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. -

Familial aplasia of the vermis Pathogenic:1 Uncertain: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:1 Benign: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

Invitae

Jan 22, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Pathogenic	0.16
Cadd	Pathogenic	32
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.31	T;.
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D;D
MetaRNN	Benign	0.0056	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.6	M;.
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.62	T
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	T
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

Other links and lift over

dbSNP: rs17089782; hg19: chr13-73409497; COSMIC: COSV58326745; COSMIC: COSV58326745;