chr3-87259754-T-A

Position:

• chr3-87259754-T-A

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.*140A>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 0.368 in 652,744 control chromosomes in the GnomAD database, including 46,591 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.33 (9644 hom., cov: 30)
  • Exomes 𝑓: 0.38 (36947 hom.)
• Consequence: POU1F1 NM_000306.4 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.696

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=-0.93).
• BP6: Variant 3-87259754-T-A is Benign according to our data. Variant chr3-87259754-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 346833.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.438 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POU1F1	NM_000306.4	c.*140A>T		3_prime_UTR_variant	6/6	ENST00000350375.7	NP_000297.1
POU1F1	NM_001122757.3	c.*140A>T		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.*140A>T		3_prime_UTR_variant	6/6	1	NM_000306.4	ENSP00000263781.2
POU1F1	ENST00000344265	c.*140A>T		3_prime_UTR_variant	6/6	5		ENSP00000342931.3

Frequencies

GnomAD3 genomes AF: 0.328 AC: 49735 AN: 151410 Hom.: 9642 Cov.: 30

Gnomad AFR AF: 0.122

Gnomad AMI AF: 0.526

Gnomad AMR AF: 0.333

Gnomad ASJ AF: 0.428

Gnomad EAS AF: 0.200

Gnomad SAS AF: 0.281

Gnomad FIN AF: 0.432

Gnomad MID AF: 0.389

Gnomad NFE AF: 0.442

Gnomad OTH AF: 0.341

GnomAD4 exome AF: 0.381 AC: 190782 AN: 501218 Hom.: 36947 Cov.: 6 AF XY: 0.378 AC XY: 100763 AN XY: 266340

Gnomad4 AFR exome AF: 0.113

Gnomad4 AMR exome AF: 0.322

Gnomad4 ASJ exome AF: 0.406

Gnomad4 EAS exome AF: 0.218

Gnomad4 SAS exome AF: 0.286

Gnomad4 FIN exome AF: 0.414

Gnomad4 NFE exome AF: 0.421

Gnomad4 OTH exome AF: 0.374

GnomAD4 genome AF: 0.328 AC: 49745 AN: 151526 Hom.: 9644 Cov.: 30 AF XY: 0.325 AC XY: 24033 AN XY: 74032

Gnomad4 AFR AF: 0.122

Gnomad4 AMR AF: 0.332

Gnomad4 ASJ AF: 0.428

Gnomad4 EAS AF: 0.200

Gnomad4 SAS AF: 0.281

Gnomad4 FIN AF: 0.432

Gnomad4 NFE AF: 0.442

Gnomad4 OTH AF: 0.342

Alfa AF: 0.247 Hom.: 651

Bravo AF: 0.312

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 12, 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	-0.93
CADD	Benign	0.066
DANN	Benign	0.19

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: rs33936108; hg19: chr3-87308904; COSMIC: COSV55461192; COSMIC: COSV55461192;