rs104893762

chr3-87260055-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The NM_000306.4(POU1F1):c.715C>T(p.Pro239Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,786 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 (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: POU1F1 NM_000306.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.57

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 Likely_pathogenic. Variant got 9 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, 0.957
• PP5: Variant 3-87260055-G-A is Pathogenic according to our data. Variant chr3-87260055-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 13609.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POU1F1	NM_000306.4	c.715C>T	p.Pro239Ser	missense_variant	6/6	ENST00000350375.7
POU1F1	NM_001122757.3	c.793C>T	p.Pro265Ser	missense_variant	6/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POU1F1	ENST00000350375.7	c.715C>T	p.Pro239Ser	missense_variant	6/6	1	NM_000306.4	P4
POU1F1	ENST00000344265.8	c.793C>T	p.Pro265Ser	missense_variant	6/6	5		A1
POU1F1	ENST00000561167.5	c.490C>T	p.Pro164Ser	missense_variant	5/5	5
POU1F1	ENST00000560656.1	c.489C>T	p.Asn163=	synonymous_variant	4/4	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461786 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727186

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: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Pituitary hormone deficiency, combined, 1 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 01, 1998

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
Cadd	Pathogenic	30
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D;.;.
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.96	D;D;D
M_CAP	Pathogenic	0.57	D
MetaRNN	Pathogenic	0.96	D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.2	H;.;.
MutationTaster	Benign	1.0	A;A;A
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-7.5	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		0.73
MutPred		0.79		Gain of glycosylation at S240 (P = 0.0142);.;.;
MVP		0.95
MPC		0.35
ClinPred		1.0	D
GERP RS		6.1
Varity_R		0.97
gMVP		0.79

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: rs104893762; hg19: chr3-87309205;