3-87260109-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000306.4(POU1F1):c.666-5G>A variant causes a splice region, 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, intron

Scores

Splicing: ADA: 0.00008690

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 0.899

Publications

2 publications found

Variant links:

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]

POU1F1 Gene-Disease associations (from GenCC):

pituitary hormone deficiency, combined, 1
Inheritance: AD, AR, SD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
combined pituitary hormone deficiencies, genetic form
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
hypothyroidism due to deficient transcription factors involved in pituitary development or function
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
isolated growth hormone deficiency type II
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

POU1F1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 198069.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0797 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000306.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POU1F1	NM_000306.4	MANE Select	c.666-5G>A		splice_region intron	N/A	NP_000297.1
	POU1F1	NM_001122757.3		c.744-5G>A		splice_region intron	N/A	NP_001116229.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
POU1F1	ENST00000350375.7	TSL:1 MANE Select	c.666-5G>A	splice_region intron	N/A	ENSP00000263781.2
POU1F1	ENST00000344265.8	TSL:5	c.744-5G>A	splice_region intron	N/A	ENSP00000342931.3
POU1F1	ENST00000561167.5	TSL:5	c.441-5G>A	splice_region intron	N/A	ENSP00000454072.1

Frequencies

GnomAD3 genomes

AF:

0.00732

AC:

1107

AN:

151212

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.0154

AC:

3746

AN:

243964

AF XY:

0.0120

show subpopulations

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 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.:

AF XY:

0.00361

AC XY:

2620

AN XY:

725518

show subpopulations

African (AFR)

AF:

0.000688

AC:

AN:

33426

American (AMR)

AF:

0.0820

AC:

3638

AN:

44390

Ashkenazi Jewish (ASJ)

AF:

0.000115

AC:

AN:

26052

East Asian (EAS)

AF:

0.0343

AC:

1356

AN:

39560

South Asian (SAS)

AF:

0.000744

AC:

AN:

85982

European-Finnish (FIN)

AF:

0.000921

AC:

AN:

53224

Middle Eastern (MID)

AF:

0.000694

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.000432

AC:

479

AN:

1109992

Other (OTH)

AF:

0.00470

AC:

283

AN:

60232

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

272

544

815

1087

1359

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

192

288

384

480

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00732

AC:

1107

AN:

151328

Hom.:

Cov.:

AF XY:

0.00830

AC XY:

613

AN XY:

73868

show subpopulations

African (AFR)

AF:

0.00102

AC:

AN:

41206

American (AMR)

AF:

0.0518

AC:

786

AN:

15180

Ashkenazi Jewish (ASJ)

AF:

0.000289

AC:

AN:

3460

East Asian (EAS)

AF:

0.0380

AC:

195

AN:

5128

South Asian (SAS)

AF:

0.00209

AC:

AN:

4776

European-Finnish (FIN)

AF:

0.00144

AC:

AN:

10422

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000575

AC:

AN:

67848

Other (OTH)

AF:

0.00903

AC:

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

103

154

206

257

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00332

Hom.:

Bravo

AF:

0.0124

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Jan 20, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jul 10, 2018

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Dec 16, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

not specified

Benign:2

Apr 17, 2015

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Pituitary hormone deficiency, combined, 1

Benign:2

Feb 14, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Frontotemporal dementia

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.78

CADD

Benign

6.9

(source)

DANN

Benign

0.90

PhyloP100

0.90

Mutation Taster

=99/1

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over