rs104893757

Variant names:

• chr3-87276392-G-A
• rs104893757
• NM_000306.4:c.71C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP2 PP3 PP5_Moderate

The NM_000306.4(POU1F1):​c.71C>T​(p.Pro24Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. P24P) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: POU1F1 NM_000306.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 7.18
• Publications: 8 publications found

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 Gene-Disease associations (from GenCC):

• pituitary hormone deficiency, combined, 1

  Inheritance: AD, AR, SD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• combined pituitary hormone deficiencies, genetic form

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hypothyroidism due to deficient transcription factors involved in pituitary development or function

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• isolated growth hormone deficiency type II

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 15 curated pathogenic missense variants (we use a threshold of 10). The gene has 3 curated benign missense variants. Gene score misZ: 0.45719 (below the threshold of 3.09). Trascript score misZ: 0.74343 (below the threshold of 3.09). GenCC associations: The gene is linked to pituitary hormone deficiency, combined, 1, isolated growth hormone deficiency type II, combined pituitary hormone deficiencies, genetic form, hypothyroidism due to deficient transcription factors involved in pituitary development or function.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.777
• PP5: Variant 3-87276392-G-A is Pathogenic according to our data. Variant chr3-87276392-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 13605.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	c.71C>T	p.Pro24Leu	missense_variant	Exon 1 of 6	ENST00000350375.7	NP_000297.1
POU1F1	NM_001122757.3	c.71C>T	p.Pro24Leu	missense_variant	Exon 1 of 6		NP_001116229.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POU1F1	ENST00000350375.7	c.71C>T	p.Pro24Leu	missense_variant	Exon 1 of 6	1	NM_000306.4	ENSP00000263781.2
POU1F1	ENST00000344265.8	c.71C>T	p.Pro24Leu	missense_variant	Exon 1 of 6	5		ENSP00000342931.3
POU1F1	ENST00000561167.5	c.71C>T	p.Pro24Leu	missense_variant	Exon 1 of 5	5		ENSP00000454072.1
POU1F1	ENST00000560656.1	c.71C>T	p.Pro24Leu	missense_variant	Exon 1 of 4	5		ENSP00000452610.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

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

- -

not provided Pathogenic:1

Dec 10, 2023

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a reduced ability to activate target genes (PMID: 12200420); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 12904605, 26612202, 16968807, 1472057, 16131601, 19609847, 12200420) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.69	D;.;.;.
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.95	D;D;D;D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.78	D;D;D;D
MetaSVM	Uncertain	-0.28	T
MutationAssessor	Benign	2.0	M;M;.;.
PhyloP100		7.2
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-2.5	N;D;D;D
REVEL	Uncertain	0.53
Sift	Uncertain	0.0010	D;D;D;D
Sift4G	Uncertain	0.0030	D;D;.;D
Polyphen		0.55	P;B;.;.
Vest4		0.78
MutPred		0.63		Loss of disorder (P = 0.0481);Loss of disorder (P = 0.0481);Loss of disorder (P = 0.0481);Loss of disorder (P = 0.0481);
MVP		0.83
MPC		0.35
ClinPred		0.98	D
GERP RS		5.4
PromoterAI		0.0019	Neutral
Varity_R		0.18
gMVP		0.76
Mutation Taster		=10/90	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs104893757; hg19: chr3-87325542;