3-87259755-A-T

Position:

• chr3-87259755-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000306.4(POU1F1):​c.*139T>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.126 in 687,338 control chromosomes in the GnomAD database, including 5,867 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (1410 hom., cov: 31)
  • Exomes 𝑓: 0.12 (4457 hom.)
• Consequence: POU1F1 NM_000306.4 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 1.45

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 3-87259755-A-T is Benign according to our data. Variant chr3-87259755-A-T is described in ClinVar as [Likely_benign]. Clinvar id is 346836.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.22 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POU1F1	NM_000306.4	c.*139T>A		3_prime_UTR_variant	6/6	ENST00000350375.7	NP_000297.1
POU1F1	NM_001122757.3	c.*139T>A		3_prime_UTR_variant	6/6		NP_001116229.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POU1F1	ENST00000350375	c.*139T>A		3_prime_UTR_variant	6/6	1	NM_000306.4	ENSP00000263781.2
POU1F1	ENST00000344265	c.*139T>A		3_prime_UTR_variant	6/6	5		ENSP00000342931.3

Frequencies

GnomAD3 genomes AF: 0.140 AC: 20208 AN: 144644 Hom.: 1409 Cov.: 31

Gnomad AFR AF: 0.160

Gnomad AMI AF: 0.104

Gnomad AMR AF: 0.119

Gnomad ASJ AF: 0.140

Gnomad EAS AF: 0.231

Gnomad SAS AF: 0.211

Gnomad FIN AF: 0.108

Gnomad MID AF: 0.141

Gnomad NFE AF: 0.125

Gnomad OTH AF: 0.151

GnomAD4 exome AF: 0.122 AC: 66285 AN: 542596 Hom.: 4457 Cov.: 7 AF XY: 0.125 AC XY: 35824 AN XY: 287086

Gnomad4 AFR exome AF: 0.150

Gnomad4 AMR exome AF: 0.0992

Gnomad4 ASJ exome AF: 0.146

Gnomad4 EAS exome AF: 0.189

Gnomad4 SAS exome AF: 0.191

Gnomad4 FIN exome AF: 0.110

Gnomad4 NFE exome AF: 0.106

Gnomad4 OTH exome AF: 0.131

GnomAD4 genome AF: 0.140 AC: 20219 AN: 144742 Hom.: 1410 Cov.: 31 AF XY: 0.141 AC XY: 10011 AN XY: 70814

Gnomad4 AFR AF: 0.160

Gnomad4 AMR AF: 0.119

Gnomad4 ASJ AF: 0.140

Gnomad4 EAS AF: 0.231

Gnomad4 SAS AF: 0.214

Gnomad4 FIN AF: 0.108

Gnomad4 NFE AF: 0.125

Gnomad4 OTH AF: 0.149

Alfa AF: 0.128 Hom.: 138

Bravo AF: 0.131

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Combined Pituitary Hormone Deficiency, Recessive Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

Frontotemporal dementia Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 19, 2021	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Pituitary hormone deficiency, combined, 1 Benign:1

Benign, 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.32
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: rs4988463; hg19: chr3-87308905; COSMIC: COSV105053721; COSMIC: COSV105053721;