3-87262160-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_000306.4(POU1F1):c.515G>A(p.Arg172Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000547 in 1,461,828 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 Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

POU1F1
NM_000306.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 7.57

Variant links:

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]

POU1F1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.977

PP5

Variant 3-87262160-C-T is Pathogenic according to our data. Variant chr3-87262160-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 13614.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POU1F1	NM_000306.4 link	c.515G>A	p.Arg172Gln	missense_variant	Exon 4 of 6	ENST00000350375.7	NP_000297.1	P28069-1
POU1F1	NM_001122757.3 link	c.593G>A	p.Arg198Gln	missense_variant	Exon 4 of 6		NP_001116229.1	P28069-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
POU1F1	ENST00000350375.7 link	c.515G>A	p.Arg172Gln	missense_variant	Exon 4 of 6	1	NM_000306.4	ENSP00000263781.2	P28069-1
POU1F1	ENST00000344265.8 link	c.593G>A	p.Arg198Gln	missense_variant	Exon 4 of 6	5		ENSP00000342931.3	P28069-2
POU1F1	ENST00000561167.5 link	c.290G>A	p.Arg97Gln	missense_variant	Exon 3 of 5	5		ENSP00000454072.1	H0YNM5
POU1F1	ENST00000560656.1 link	c.440-2056G>A		intron_variant	Intron 3 of 3	5		ENSP00000452610.1	H0YK06

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251290

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135806

show subpopulations

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:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000547

AC:

AN:

1461828

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727214

show subpopulations

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000630

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Pituitary hormone deficiency, combined, 1

Pathogenic:3

May 22, 2022

3billion

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.84; 3Cnet: 0.80). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with POU1F1 related disorder (ClinVar ID: VCV000013614 / PMID: 15928241). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 15928241). The variant has been reported to co-segregate with the disease in at least 3 similarly affected relatives/individuals in the same family or similarly affected unrelated family (PMID:15928241, 27541381). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline. -

Aug 01, 2005

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

May 21, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

POU1F1-related disorder

Pathogenic:1

Aug 05, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The POU1F1 c.515G>A variant is predicted to result in the amino acid substitution p.Arg172Gln. This variant has been reported in the compound heterozygous state with a second pathogenic POU1F1 variant in two siblings with pituitary hormone deficiency (Turton et al. 2005. PubMed ID: 15928241). It has also been reported in the homozygous state in three siblings with combined pituitary hormone deficiency (Shamseldin et al. 2016. PubMed ID: 27541381). Experimental studies suggest that the Arg172Gln substitution leads to a reduction in transactivation by POU1F1 (Turton et al. 2005. PubMed ID: 15928241). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as likely pathogenic. -

Combined pituitary hormone deficiencies, genetic form

Pathogenic:1

Jul 26, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: POU1F1 c.515G>A (p.Arg172Gln) results in a conservative amino acid change located in the POU-specific domain (IPR000327) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251290 control chromosomes (gnomAD). c.515G>A has been reported in the literature in two compound heterozygous siblings and in three homozygous siblings affected with Combined Pituitary Hormone Deficiency from two different families (Turton_2005, Shamseldin_2016). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function and found that the variant results in impaired transactivaton (exhibiting 50% to <10% transactivation activity compared to the WT) at POU-binding sites in the GH-1, PRL, and POU1F1 promoters (Turton_2005). The following publications have been ascertained in the context of this evaluation (PMID: 27541381, 15928241). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and both classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided

Pathogenic:1

Sep 28, 2017

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The R172Q variant in the POU1F1 gene has been reported previously in the compound heterozygous and homozygous states in association with combined pituitary hormone deficiency (Turton et al., 2005; Shamseldin et al., 2016). The R172Q variant is observed in 1/66724 (0.002%) alleles from individuals of non-Finnish European background in the ExAC dataset (Lek et al., 2016). The R172Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret R172Q as a likely pathogenic variant. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.44

BayesDel_noAF

Pathogenic

0.40

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.96

D;.;.

Eigen

Pathogenic

0.95

Eigen_PC

Pathogenic

0.93

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.99

D;D;D

M_CAP

Uncertain

0.22

MetaRNN

Pathogenic

0.98

D;D;D

MetaSVM

Pathogenic

0.83

MutationAssessor

Pathogenic

2.9

M;.;.

PrimateAI

Pathogenic

0.85

PROVEAN

Uncertain

-3.7

D;D;D

REVEL

Pathogenic

0.84

Sift

Pathogenic

0.0

D;D;D

Sift4G

Pathogenic

0.0

D;D;.

Polyphen

1.0

D;D;.

Vest4

0.98

MutPred

0.95

Loss of MoRF binding (P = 0.0876);.;.;

MVP

0.95

MPC

0.35

ClinPred

1.0

GERP RS

6.0

Varity_R

0.94

gMVP

0.81

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