3-87264299-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PP3_StrongPP5_Moderate

The NM_000306.4(POU1F1):c.428G>A(p.Arg143Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,457,598 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 (★). Synonymous variant affecting the same amino acid position (i.e. R143R) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

POU1F1
NM_000306.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 7.23

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 10 ACMG points.

PM1

In a domain POU-specific (size 74) in uniprot entity PIT1_HUMAN there are 9 pathogenic changes around while only 2 benign (82%) in NM_000306.4

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.981

PP5

Variant 3-87264299-C-T is Pathogenic according to our data. Variant chr3-87264299-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 13606.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POU1F1	NM_000306.4 link	c.428G>A	p.Arg143Gln	missense_variant	Exon 3 of 6	ENST00000350375.7	NP_000297.1	P28069-1
POU1F1	NM_001122757.3 link	c.506G>A	p.Arg169Gln	missense_variant	Exon 3 of 6		NP_001116229.1	P28069-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
POU1F1	ENST00000350375.7 link	c.428G>A	p.Arg143Gln	missense_variant	Exon 3 of 6	1	NM_000306.4	ENSP00000263781.2	P28069-1
POU1F1	ENST00000344265.8 link	c.506G>A	p.Arg169Gln	missense_variant	Exon 3 of 6	5		ENSP00000342931.3	P28069-2
POU1F1	ENST00000560656.1 link	c.428G>A	p.Arg143Gln	missense_variant	Exon 3 of 4	5		ENSP00000452610.1	H0YK06
POU1F1	ENST00000561167.5 link	c.215-2064G>A		intron_variant	Intron 2 of 4	5		ENSP00000454072.1	H0YNM5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000399

AC:

AN:

250860

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135616

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.86e-7

AC:

AN:

1457598

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

725344

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Pituitary hormone deficiency, combined, 1

Pathogenic:1

Dec 15, 1992

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Combined pituitary hormone deficiencies, genetic form

Pathogenic:1

Jan 08, 2025

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.428G>A (p.Arg143Gln) results in a conservative amino acid change located in the POU-specific (POUs) domain 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 250860 control chromosomes. c.428G>A has been reported in the literature in multiple homozygous individuals affected with Combined Pituitary Hormone Deficiency (examples: Ohta_1992 and Aykut_2014). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence that this variant reduced transactivation of the GH or prolactin reporter genes (Cohen_2006). The following publications have been ascertained in the context of this evaluation (PMID 24025721, 1472057, 16263824). ClinVar contains an entry for this variant (Variation ID: 13606). Based on the evidence outlined above, the variant was classified as pathogenic for autosomal recessive Combined Pituitary Hormone Deficiency. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.32

BayesDel_noAF

Pathogenic

0.40

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.95

D;.;.

Eigen

Pathogenic

0.92

Eigen_PC

Pathogenic

0.87

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

D;D;D

M_CAP

Uncertain

0.28

MetaRNN

Pathogenic

0.98

D;D;D

MetaSVM

Pathogenic

0.89

MutationAssessor

Pathogenic

2.9

M;.;.

PrimateAI

Uncertain

0.77

PROVEAN

Uncertain

-3.6

D;D;N

REVEL

Pathogenic

0.89

Sift

Pathogenic

0.0

D;D;D

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

D;D;.

Vest4

0.97

MutPred

0.94

Loss of MoRF binding (P = 0.039);.;Loss of MoRF binding (P = 0.039);

MVP

0.95

MPC

0.36

ClinPred

1.0

GERP RS

5.5

Varity_R

0.98

gMVP

0.88

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.14

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