3-87259753-T-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BS1_Supporting

The NM_000306.4(POU1F1):c.*141A>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000759 in 686,254 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00062 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00080 (1 hom.)
• Consequence: POU1F1 NM_000306.4 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.541

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_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00062 (94/151710) while in subpopulation EAS AF= 0.00347 (18/5186). AF 95% confidence interval is 0.00224. There are 0 homozygotes in gnomad4. There are 45 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POU1F1	NM_000306.4	c.*141A>T		3_prime_UTR_variant	6/6	ENST00000350375.7
POU1F1	NM_001122757.3	c.*141A>T		3_prime_UTR_variant	6/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POU1F1	ENST00000350375.7	c.*141A>T		3_prime_UTR_variant	6/6	1	NM_000306.4	P4
POU1F1	ENST00000344265.8	c.*141A>T		3_prime_UTR_variant	6/6	5		A1

Frequencies

GnomAD3 genomes AF: 0.000620 AC: 94 AN: 151592 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000970

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000263

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00346

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.000954

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000766

Gnomad OTH AF: 0.00144

GnomAD4 exome AF: 0.000799 AC: 427 AN: 534544 Hom.: 1 Cov.: 7 AF XY: 0.000786 AC XY: 223 AN XY: 283846

Gnomad4 AFR exome AF: 0.000363

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00278

Gnomad4 SAS exome AF: 0.000557

Gnomad4 FIN exome AF: 0.00191

Gnomad4 NFE exome AF: 0.000646

Gnomad4 OTH exome AF: 0.000803

GnomAD4 genome AF: 0.000620 AC: 94 AN: 151710 Hom.: 0 Cov.: 33 AF XY: 0.000607 AC XY: 45 AN XY: 74192

Gnomad4 AFR AF: 0.0000968

Gnomad4 AMR AF: 0.000263

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00347

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.000954

Gnomad4 NFE AF: 0.000766

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000756 Hom.: 0

Bravo AF: 0.000453

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Pituitary hormone deficiency, combined, 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
Cadd	Benign	0.23
Dann	Benign	0.57

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: rs552876873; hg19: chr3-87308903; COSMIC: COSV55463224; COSMIC: COSV55463224;