3-87259754-T-TA

Variant names:

• chr3-87259754-T-TA
• rs368061882
• NM_000306.4:c.*139dupT

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The NM_000306.4(POU1F1):​c.*139dupT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0216 in 653,884 control chromosomes in the GnomAD database, including 190 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.026 (68 hom., cov: 31)
  • Exomes 𝑓: 0.020 (122 hom.)
• Consequence: POU1F1 NM_000306.4 3_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 1.45
• Publications: 0 publications found

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: AR, SD, AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, 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

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP6: Variant 3-87259754-T-TA is Benign according to our data. Variant chr3-87259754-T-TA is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 346834.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0258 (3906/151636) while in subpopulation AFR AF = 0.0387 (1601/41358). AF 95% confidence interval is 0.0371. There are 68 homozygotes in GnomAd4. There are 1887 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 68 AD,AR,SD gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POU1F1	NM_000306.4	MANE Select	c.*139dupT		3_prime_UTR	Exon 6 of 6	NP_000297.1	P28069-1
	POU1F1	NM_001122757.3		c.*139dupT		3_prime_UTR	Exon 6 of 6	NP_001116229.1	P28069-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POU1F1	ENST00000350375.7	TSL:1 MANE Select	c.*139dupT		3_prime_UTR	Exon 6 of 6	ENSP00000263781.2	P28069-1
	POU1F1	ENST00000344265.8	TSL:5	c.*139dupT		3_prime_UTR	Exon 6 of 6	ENSP00000342931.3	P28069-2
	POU1F1	ENST00000561167.5	TSL:5	c.*140dupT		downstream_gene	N/A	ENSP00000454072.1	H0YNM5

Frequencies

GnomAD3 genomes AF: 0.0257 AC: 3899 AN: 151520 Hom.: 68 Cov.: 31

Gnomad AFR AF: 0.0387

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0220

Gnomad ASJ AF: 0.00779

Gnomad EAS AF: 0.00443

Gnomad SAS AF: 0.00809

Gnomad FIN AF: 0.0254

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0229

Gnomad OTH AF: 0.0255

GnomAD4 exome AF: 0.0204 AC: 10227 AN: 502248 Hom.: 122 Cov.: 7 AF XY: 0.0196 AC XY: 5242 AN XY: 266874

African (AFR) AF: 0.0427 AC: 569 AN: 13320

American (AMR) AF: 0.0192 AC: 356 AN: 18566

Ashkenazi Jewish (ASJ) AF: 0.00694 AC: 103 AN: 14840

East Asian (EAS) AF: 0.00755 AC: 230 AN: 30452

South Asian (SAS) AF: 0.00827 AC: 387 AN: 46804

European-Finnish (FIN) AF: 0.0241 AC: 767 AN: 31866

Middle Eastern (MID) AF: 0.0199 AC: 42 AN: 2110

European-Non Finnish (NFE) AF: 0.0227 AC: 7175 AN: 316662

Other (OTH) AF: 0.0216 AC: 598 AN: 27628

GnomAD4 genome AF: 0.0258 AC: 3906 AN: 151636 Hom.: 68 Cov.: 31 AF XY: 0.0255 AC XY: 1887 AN XY: 74096

African (AFR) AF: 0.0387 AC: 1601 AN: 41358

American (AMR) AF: 0.0222 AC: 337 AN: 15182

Ashkenazi Jewish (ASJ) AF: 0.00779 AC: 27 AN: 3466

East Asian (EAS) AF: 0.00444 AC: 23 AN: 5178

South Asian (SAS) AF: 0.00809 AC: 39 AN: 4818

European-Finnish (FIN) AF: 0.0254 AC: 265 AN: 10450

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.0229 AC: 1554 AN: 67878

Other (OTH) AF: 0.0252 AC: 53 AN: 2104

Alfa AF: 0.00562 Hom.: 2

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Combined Pituitary Hormone Deficiency, Recessive (1)
-	-	1	Frontotemporal dementia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.5
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs368061882; hg19: chr3-87308904;