rs104893764

Positions:

chr3-87260082-C-T

Variant summary

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

The NM_000306.4(POU1F1):c.688G>A(p.Glu230Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000093 in 1,613,616 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: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000096 ( 0 hom. )

Consequence

POU1F1
NM_000306.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 7.54

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, 0.976

PP5

Variant 3-87260082-C-T is Pathogenic according to our data. Variant chr3-87260082-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 13613.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-87260082-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POU1F1	NM_000306.4 linkuse as main transcript	c.688G>A	p.Glu230Lys	missense_variant	6/6	ENST00000350375.7	NP_000297.1
POU1F1	NM_001122757.3 linkuse as main transcript	c.766G>A	p.Glu256Lys	missense_variant	6/6		NP_001116229.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POU1F1	ENST00000350375.7 linkuse as main transcript	c.688G>A	p.Glu230Lys	missense_variant	6/6	1	NM_000306.4	ENSP00000263781	P4	P28069-1
POU1F1	ENST00000560656.1 linkuse as main transcript	c.462G>A	p.Trp154Ter	stop_gained	4/4	5		ENSP00000452610
POU1F1	ENST00000344265.8 linkuse as main transcript	c.766G>A	p.Glu256Lys	missense_variant	6/6	5		ENSP00000342931	A1	P28069-2
POU1F1	ENST00000561167.5 linkuse as main transcript	c.463G>A	p.Glu155Lys	missense_variant	5/5	5		ENSP00000454072

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

151970

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000240

AC:

AN:

250200

Hom.:

AF XY:

0.0000296

AC XY:

AN XY:

135272

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000290

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:

0.0000443

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000958

AC:

AN:

1461646

Hom.:

Cov.:

AF XY:

0.0000124

AC XY:

AN XY:

727114

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

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:

0.0000117

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000658

AC:

AN:

151970

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74206

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000425

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000178

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Pituitary hormone deficiency, combined, 1

Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 01, 2005	- -
Pathogenic, criteria provided, single submitter	clinical testing	Department Of Genetics, Sultan Qaboos University Hospital, Sultan Qaboos University	Jun 30, 2022	- -

not provided

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 27, 2023	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate a damaging effect on transcription activation (Liang et al., 1995; Turton et al., 2005); This variant is associated with the following publications: (PMID: 19837867, 36344539, 31702014, 34815942, 20852587, 15928241, 7592721, 11924936, 33742319) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 13, 2023	Experimental studies have shown that this missense change affects POU1F1 function (PMID: 15928241). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 230 of the POU1F1 protein (p.Glu230Lys). This variant is present in population databases (rs104893764, gnomAD 0.005%). This missense change has been observed in individuals with autosomal recessive combined pituitary hormone deficiency (PMID: 11924936, 15928241). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 13613). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on POU1F1 protein function. For these reasons, this variant has been classified as Pathogenic. -

POU1F1-related disorder

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 27, 2024

The POU1F1 c.688G>A variant is predicted to result in the amino acid substitution p.Glu230Lys. This variant has been reported in the homozygous and compound heterozygous states in multiple patients with POU1F1 related pituitary hormone deficiency, and functional studies support its pathogenicity (Gat-Yablonski et al. 2002. PubMed ID: 11924936; Turton et al. 2005. PubMed ID: 15928241). This variant is reported in 0.0044% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.45

BayesDel_noAF

Pathogenic

0.54

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.94

D;.;.

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.98

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.92

D;D;D

MetaRNN

Pathogenic

0.98

D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.6

M;.;.

MutationTaster

Benign

1.0

A;A;A

PrimateAI

Pathogenic

0.82

PROVEAN

Uncertain

-3.8

D;D;D

REVEL

Pathogenic

0.95

Sift

Pathogenic

0.0

D;D;D

Sift4G

Pathogenic

0.0

D;D;.

Polyphen

1.0

D;D;.

Vest4

0.93

MutPred

0.87

Gain of MoRF binding (P = 0.004);.;.;

MVP

0.99

MPC

0.36

ClinPred

0.99

GERP RS

6.1

Varity_R

0.96

gMVP

0.77

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