3-87259754-T-TA

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The NM_000306.4(POU1F1):c.*139_*140insT 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

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 -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 id is 346834.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
• 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 male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 68 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POU1F1	NM_000306.4	c.*139_*140insT		3_prime_UTR_variant	6/6	ENST00000350375.7
POU1F1	NM_001122757.3	c.*139_*140insT		3_prime_UTR_variant	6/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POU1F1	ENST00000350375.7	c.*139_*140insT		3_prime_UTR_variant	6/6	1	NM_000306.4	P4
POU1F1	ENST00000344265.8	c.*139_*140insT		3_prime_UTR_variant	6/6	5		A1

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

Gnomad4 AFR exome AF: 0.0427

Gnomad4 AMR exome AF: 0.0192

Gnomad4 ASJ exome AF: 0.00694

Gnomad4 EAS exome AF: 0.00755

Gnomad4 SAS exome AF: 0.00827

Gnomad4 FIN exome AF: 0.0241

Gnomad4 NFE exome AF: 0.0227

Gnomad4 OTH exome AF: 0.0216

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

Gnomad4 AFR AF: 0.0387

Gnomad4 AMR AF: 0.0222

Gnomad4 ASJ AF: 0.00779

Gnomad4 EAS AF: 0.00444

Gnomad4 SAS AF: 0.00809

Gnomad4 FIN AF: 0.0254

Gnomad4 NFE AF: 0.0229

Gnomad4 OTH AF: 0.0252

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Combined Pituitary Hormone Deficiency, Recessive Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Frontotemporal dementia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

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: rs368061882; hg19: chr3-87308904;