rs104893765

Positions:

• chr3-87262160-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_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
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 7.57

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 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/exons	MANE	Protein	UniProt
POU1F1	NM_000306.4	c.515G>A	p.Arg172Gln	missense_variant	4/6	ENST00000350375.7	NP_000297.1
POU1F1	NM_001122757.3	c.593G>A	p.Arg198Gln	missense_variant	4/6		NP_001116229.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POU1F1	ENST00000350375.7	c.515G>A	p.Arg172Gln	missense_variant	4/6	1	NM_000306.4	ENSP00000263781.2
POU1F1	ENST00000344265.8	c.593G>A	p.Arg198Gln	missense_variant	4/6	5		ENSP00000342931.3
POU1F1	ENST00000561167.5	c.290G>A	p.Arg97Gln	missense_variant	3/5	5		ENSP00000454072.1
POU1F1	ENST00000560656.1	c.440-2056G>A		intron_variant		5		ENSP00000452610.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251290 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: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461828 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727214

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.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Pituitary hormone deficiency, combined, 1 Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	3billion	May 22, 2022	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. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 01, 2005	- -

POU1F1-related disorder Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 05, 2024

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

Pathogenic, criteria provided, single submitter

clinical testing

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

Jul 26, 2023

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

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Sep 28, 2017

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	D
BayesDel_noAF	Pathogenic	0.40
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.96	D;.;.
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.98	D;D;D
MetaSVM	Pathogenic	0.83	D
MutationAssessor	Pathogenic	2.9	M;.;.
PrimateAI	Pathogenic	0.85	D
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	D
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

Other links and lift over

dbSNP: rs104893765; hg19: chr3-87311310; COSMIC: COSV60156802;