3-87259959-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The NM_000306.4(POU1F1):c.811C>T(p.Arg271Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: POU1F1 NM_000306.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 2.76

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a DNA_binding_region Homeobox (size 59) in uniprot entity PIT1_HUMAN there are 6 pathogenic changes around while only 1 benign (86%) in NM_000306.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.93

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POU1F1	NM_000306.4	c.811C>T	p.Arg271Trp	missense_variant	6/6	ENST00000350375.7
POU1F1	NM_001122757.3	c.889C>T	p.Arg297Trp	missense_variant	6/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POU1F1	ENST00000350375.7	c.811C>T	p.Arg271Trp	missense_variant	6/6	1	NM_000306.4	P4
POU1F1	ENST00000344265.8	c.889C>T	p.Arg297Trp	missense_variant	6/6	5		A1
POU1F1	ENST00000561167.5	c.586C>T	p.Arg196Trp	missense_variant	5/5	5
POU1F1	ENST00000560656.1	c.*75C>T		3_prime_UTR_variant	4/4	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Pituitary hormone deficiency, combined, 1 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Aug 01, 2005

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Nov 16, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.51
Cadd	Pathogenic	29
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.97	D;.;.
Eigen	Pathogenic	0.72
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Benign	0.73	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Pathogenic	0.60	D
MetaRNN	Pathogenic	0.93	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.8	H;.;.
MutationTaster	Benign	1.0	A;A;A
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-7.3	D;D;D
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;.
Polyphen		1.0	D;D;.
Vest4		0.90
MutPred		0.75		Loss of disorder (P = 0.0037);.;.;
MVP		0.98
MPC		0.35
ClinPred		1.0	D
GERP RS		3.0
Varity_R		0.96
gMVP		0.63

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: rs104893755; hg19: chr3-87309109; COSMIC: COSV55461969; COSMIC: COSV55461969;