NM_000306.4:c.775dupA
Variant names:
Variant summary
Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PVS1_StrongPM2PP5
The NM_000306.4(POU1F1):c.775dupA(p.Arg259LysfsTer27) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,838 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (no stars).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )
Consequence
POU1F1
NM_000306.4 frameshift
NM_000306.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 1.38
Publications
1 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, 1Inheritance: AR, SD, AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
- combined pituitary hormone deficiencies, genetic formInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- hypothyroidism due to deficient transcription factors involved in pituitary development or functionInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- isolated growth hormone deficiency type IIInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
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ACMG classification
Classification was made for transcript
Our verdict: Likely_pathogenic. The variant received 7 ACMG points.
PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 5 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 3-87259994-C-CT is Pathogenic according to our data. Variant chr3-87259994-C-CT is described in ClinVar as Pathogenic. ClinVar VariationId is 13615.Status of the report is no_assertion_criteria_provided, 0 stars.
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.775dupA | p.Arg259LysfsTer27 | frameshift | Exon 6 of 6 | NP_000297.1 | P28069-1 | |
| POU1F1 | NM_001122757.3 | c.853dupA | p.Arg285LysfsTer27 | frameshift | 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.775dupA | p.Arg259LysfsTer27 | frameshift | Exon 6 of 6 | ENSP00000263781.2 | P28069-1 | |
| POU1F1 | ENST00000344265.8 | TSL:5 | c.853dupA | p.Arg285LysfsTer27 | frameshift | Exon 6 of 6 | ENSP00000342931.3 | P28069-2 | |
| POU1F1 | ENST00000561167.5 | TSL:5 | c.550dupA | p.Arg184LysfsTer27 | frameshift | Exon 5 of 5 | ENSP00000454072.1 | H0YNM5 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461838Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 727216 show subpopulations
GnomAD4 exome
AF:
AC:
1
AN:
1461838
Hom.:
Cov.:
31
AF XY:
AC XY:
1
AN XY:
727216
show subpopulations
African (AFR)
AF:
AC:
0
AN:
33480
American (AMR)
AF:
AC:
0
AN:
44724
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
26134
East Asian (EAS)
AF:
AC:
0
AN:
39686
South Asian (SAS)
AF:
AC:
0
AN:
86254
European-Finnish (FIN)
AF:
AC:
0
AN:
53420
Middle Eastern (MID)
AF:
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
AC:
1
AN:
1111980
Other (OTH)
AF:
AC:
0
AN:
60392
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.575
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome
GnomAD4 genome
Cov.:
32
ClinVar
ClinVar submissions
View on ClinVar Significance:Pathogenic
Revision:no assertion criteria provided
Pathogenic
VUS
Benign
Condition
1
-
-
Pituitary hormone deficiency, combined, 1 (1)
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
PhyloP100
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
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