rs104893754

Positions:

• chr3-87262161-G-A
• chr3-87262161-G-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_000306.4(POU1F1):​c.514C>T​(p.Arg172Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000479 in 1,461,796 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: POU1F1 NM_000306.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 4.60

Genes affected

POU1F1 (HGNC:9210): (POU class 1 homeobox 1) This gene encodes a member of the POU family of transcription factors that regulate mammalian development. The protein regulates expression of several genes involved in pituitary development and hormone expression. Mutations in this genes result in combined pituitary hormone deficiency. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-87262161-G-A is Pathogenic according to our data. Variant chr3-87262161-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 13602.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POU1F1	NM_000306.4	c.514C>T	p.Arg172Ter	stop_gained	4/6	ENST00000350375.7	NP_000297.1
POU1F1	NM_001122757.3	c.592C>T	p.Arg198Ter	stop_gained	4/6		NP_001116229.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POU1F1	ENST00000350375.7	c.514C>T	p.Arg172Ter	stop_gained	4/6	1	NM_000306.4	ENSP00000263781	P4
POU1F1	ENST00000344265.8	c.592C>T	p.Arg198Ter	stop_gained	4/6	5		ENSP00000342931	A1
POU1F1	ENST00000561167.5	c.289C>T	p.Arg97Ter	stop_gained	3/5	5		ENSP00000454072
POU1F1	ENST00000560656.1	c.440-2057C>T		intron_variant		5		ENSP00000452610

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251292 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135806

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461796 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727196

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Pituitary hormone deficiency, combined, 1 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 01, 1992

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 09, 2023

This sequence change creates a premature translational stop signal (p.Arg172*) in the POU1F1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in POU1F1 are known to be pathogenic (PMID: 1472057, 9392392, 15844473, 15928241). This variant is present in population databases (rs104893754, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with POU1F1-related conditions (PMID: 1302000, 9485179, 34006472). This variant is also known as p.Arg198Ter. ClinVar contains an entry for this variant (Variation ID: 13602). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.65
CADD	Pathogenic	37
DANN	Uncertain	1.0
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Uncertain	0.96	D
MutationTaster	Benign	1.0	A;A;A
Vest4		0.97
GERP RS		5.1

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: rs104893754; hg19: chr3-87311311;