rs17089782

Variant names:

• chr13-72835359-G-A
• rs17089782
• NM_006346.4:c.1214G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 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:3
• Conservation: PhyloP100: 8.93
• Publications: 13 publications found

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

ACMG classification

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 VariationId is 217689.
• 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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006346.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIBF1	NM_006346.4	MANE Select	c.1214G>A	p.Arg405Gln	missense	Exon 9 of 18	NP_006337.2
	PIBF1	NM_001349655.2		c.1214G>A	p.Arg405Gln	missense	Exon 9 of 19	NP_001336584.1
	PIBF1	NR_146205.2		n.1501G>A		non_coding_transcript_exon	Exon 9 of 18

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIBF1	ENST00000326291.11	TSL:1 MANE Select	c.1214G>A	p.Arg405Gln	missense	Exon 9 of 18	ENSP00000317144.6
	PIBF1	ENST00000617689.4	TSL:1	c.1214G>A	p.Arg405Gln	missense	Exon 9 of 16	ENSP00000478697.1
	PIBF1	ENST00000615625.1	TSL:1	c.-145G>A		5_prime_UTR	Exon 2 of 9	ENSP00000483286.1

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

GnomAD2 exomes AF: 0.0148 AC: 2871 AN: 194276 AF XY: 0.0120

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

African (AFR) AF: 0.000705 AC: 21 AN: 29794

American (AMR) AF: 0.0882 AC: 2758 AN: 31266

Ashkenazi Jewish (ASJ) AF: 0.000628 AC: 15 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: 3 AN: 52288

Middle Eastern (MID) AF: 0.000364 AC: 2 AN: 5494

European-Non Finnish (NFE) AF: 0.000125 AC: 136 AN: 1091692

Other (OTH) AF: 0.00545 AC: 315 AN: 57752

GnomAD4 genome AF: 0.00832 AC: 1203 AN: 144666 Hom.: 33 Cov.: 32 AF XY: 0.00933 AC XY: 657 AN XY: 70402

African (AFR) AF: 0.00195 AC: 76 AN: 38882

American (AMR) AF: 0.0535 AC: 785 AN: 14684

Ashkenazi Jewish (ASJ) AF: 0.000299 AC: 1 AN: 3346

East Asian (EAS) AF: 0.0545 AC: 268 AN: 4920

South Asian (SAS) AF: 0.00601 AC: 27 AN: 4492

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9160

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 286

European-Non Finnish (NFE) AF: 0.000333 AC: 22 AN: 66002

Other (OTH) AF: 0.0120 AC: 24 AN: 1994

Alfa AF: 0.00401 Hom.: 81

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

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	2	1	Joubert syndrome 33 (4)
1	1	-	Joubert syndrome (2)
-	1	1	not specified (2)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

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
MetaRNN	Benign	0.0056	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		8.9
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-3.4	D
REVEL	Uncertain	0.41
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.029	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
Mutation Taster		=77/23	disease causing (ClinVar)

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