3-87259982-CA-C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_000306.4(POU1F1):c.787del(p.Cys263AlafsTer10) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: POU1F1 NM_000306.4 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 8.91

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 8 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.102 CDS is truncated, and there are 2 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-87259982-CA-C is Pathogenic according to our data. Variant chr3-87259982-CA-C is described in ClinVar as [Pathogenic]. Clinvar id is 2790971.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POU1F1	NM_000306.4	c.787del	p.Cys263AlafsTer10	frameshift_variant	6/6	ENST00000350375.7
POU1F1	NM_001122757.3	c.865del	p.Cys289AlafsTer10	frameshift_variant	6/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POU1F1	ENST00000350375.7	c.787del	p.Cys263AlafsTer10	frameshift_variant	6/6	1	NM_000306.4	P4
POU1F1	ENST00000344265.8	c.865del	p.Cys289AlafsTer10	frameshift_variant	6/6	5		A1
POU1F1	ENST00000561167.5	c.562del	p.Cys188AlafsTer10	frameshift_variant	5/5	5
POU1F1	ENST00000560656.1	c.*51del		3_prime_UTR_variant	4/4	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Sep 06, 2023

This sequence change creates a premature translational stop signal (p.Cys263Alafs*10) in the POU1F1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 29 amino acid(s) of the POU1F1 protein. For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the POU1F1 protein in which other variant(s) (p.Arg265Trp) have been determined to be pathogenic (PMID: 22010633, 27541381, 33742319). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. This variant has not been reported in the literature in individuals affected with POU1F1-related conditions. This variant is not present in population databases (gnomAD no frequency). -

Computational scores

Source: dbNSFP v4.3

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-87309132;