3-87260109-C-T

Position:

• chr3-87260109-C-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.666-5G>A variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00435 in 1,609,948 control chromosomes in the GnomAD database, including 245 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0073 (34 hom., cov: 32)
  • Exomes 𝑓: 0.0040 (211 hom.)
• Consequence: POU1F1 NM_000306.4 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00008690
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.899

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=-0.78).
• BP6: Variant 3-87260109-C-T is Benign according to our data. Variant chr3-87260109-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 198069.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-87260109-C-T is described in Lovd as [Benign].
• BA1: GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0797 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POU1F1	NM_000306.4	c.666-5G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000350375.7
POU1F1	NM_001122757.3	c.744-5G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POU1F1	ENST00000350375.7	c.666-5G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_000306.4	P4
POU1F1	ENST00000344265.8	c.744-5G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5		A1
POU1F1	ENST00000560656.1	c.440-5G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5
POU1F1	ENST00000561167.5	c.441-5G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.00732 AC: 1107 AN: 151212 Hom.: 34 Cov.: 32

Gnomad AFR AF: 0.00102

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0518

Gnomad ASJ AF: 0.000289

Gnomad EAS AF: 0.0379

Gnomad SAS AF: 0.00209

Gnomad FIN AF: 0.00144

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000575

Gnomad OTH AF: 0.00913

GnomAD3 exomes AF: 0.0154 AC: 3746 AN: 243964 Hom.: 158 AF XY: 0.0120 AC XY: 1592 AN XY: 132210

Gnomad AFR exome AF: 0.000722

Gnomad AMR exome AF: 0.0836

Gnomad ASJ exome AF: 0.000202

Gnomad EAS exome AF: 0.0409

Gnomad SAS exome AF: 0.000627

Gnomad FIN exome AF: 0.00112

Gnomad NFE exome AF: 0.000585

Gnomad OTH exome AF: 0.00962

GnomAD4 exome AF: 0.00404 AC: 5899 AN: 1458620 Hom.: 211 Cov.: 31 AF XY: 0.00361 AC XY: 2620 AN XY: 725518

Gnomad4 AFR exome AF: 0.000688

Gnomad4 AMR exome AF: 0.0820

Gnomad4 ASJ exome AF: 0.000115

Gnomad4 EAS exome AF: 0.0343

Gnomad4 SAS exome AF: 0.000744

Gnomad4 FIN exome AF: 0.000921

Gnomad4 NFE exome AF: 0.000432

Gnomad4 OTH exome AF: 0.00470

GnomAD4 genome AF: 0.00732 AC: 1107 AN: 151328 Hom.: 34 Cov.: 32 AF XY: 0.00830 AC XY: 613 AN XY: 73868

Gnomad4 AFR AF: 0.00102

Gnomad4 AMR AF: 0.0518

Gnomad4 ASJ AF: 0.000289

Gnomad4 EAS AF: 0.0380

Gnomad4 SAS AF: 0.00209

Gnomad4 FIN AF: 0.00144

Gnomad4 NFE AF: 0.000575

Gnomad4 OTH AF: 0.00903

Alfa AF: 0.00196 Hom.: 4

Bravo AF: 0.0124

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 10, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 16, 2019	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 17, 2015	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Pituitary hormone deficiency, combined, 1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Feb 14, 2022	- -
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. -

Combined Pituitary Hormone Deficiency, Recessive Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Frontotemporal dementia Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	6.9
DANN	Benign	0.90

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000087
dbscSNV1_RF	Benign	0.028
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: rs76296626; hg19: chr3-87309259;