NM_000306.4:c.*147dupA

Variant names:

• chr3-87259746-C-CT
• rs369739158
• NM_000306.4:c.*147dupA

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BS1_Supporting BS2

The NM_000306.4(POU1F1):​c.*147dupA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00224 in 655,202 control chromosomes in the GnomAD database, including 14 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0067 (10 hom., cov: 33)
  • Exomes 𝑓: 0.00091 (4 hom.)
• Consequence: POU1F1 NM_000306.4 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0510
• 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: Likely_benign. The variant received -5 ACMG points.

• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00665 (1006/151182) while in subpopulation AFR AF = 0.0228 (938/41140). AF 95% confidence interval is 0.0216. There are 10 homozygotes in GnomAd4. There are 488 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 10 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.*147dupA		3_prime_UTR	Exon 6 of 6	NP_000297.1	P28069-1
	POU1F1	NM_001122757.3		c.*147dupA		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.*147dupA		3_prime_UTR	Exon 6 of 6	ENSP00000263781.2	P28069-1
	POU1F1	ENST00000344265.8	TSL:5	c.*147dupA		3_prime_UTR	Exon 6 of 6	ENSP00000342931.3	P28069-2
	POU1F1	ENST00000561167.5	TSL:5	c.*148dupA		downstream_gene	N/A	ENSP00000454072.1	H0YNM5

Frequencies

GnomAD3 genomes AF: 0.00667 AC: 1007 AN: 151076 Hom.: 10 Cov.: 33

Gnomad AFR AF: 0.0229

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00258

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000624

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.000207

Gnomad OTH AF: 0.00481

GnomAD4 exome AF: 0.000915 AC: 461 AN: 504020 Hom.: 4 Cov.: 6 AF XY: 0.000786 AC XY: 211 AN XY: 268326

African (AFR) AF: 0.0208 AC: 276 AN: 13284

American (AMR) AF: 0.00163 AC: 30 AN: 18378

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14598

East Asian (EAS) AF: 0.0000992 AC: 3 AN: 30228

South Asian (SAS) AF: 0.000389 AC: 18 AN: 46246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 31338

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2116

European-Non Finnish (NFE) AF: 0.000312 AC: 100 AN: 320212

Other (OTH) AF: 0.00123 AC: 34 AN: 27620

GnomAD4 genome AF: 0.00665 AC: 1006 AN: 151182 Hom.: 10 Cov.: 33 AF XY: 0.00661 AC XY: 488 AN XY: 73866

African (AFR) AF: 0.0228 AC: 938 AN: 41140

American (AMR) AF: 0.00257 AC: 39 AN: 15146

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5166

South Asian (SAS) AF: 0.000625 AC: 3 AN: 4802

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10376

Middle Eastern (MID) AF: 0.00345 AC: 1 AN: 290

European-Non Finnish (NFE) AF: 0.000207 AC: 14 AN: 67786

Other (OTH) AF: 0.00477 AC: 10 AN: 2098

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.051
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: rs369739158; hg19: chr3-87308896; COSMIC: COSV99773505; COSMIC: COSV99773505;