rs1553426479
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_StrongPM2PP5_Moderate
The NM_006236.3(POU3F3):c.1197del(p.Ile400SerfsTer16) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★).
Frequency
Genomes: not found (cov: 31)
Consequence
POU3F3
NM_006236.3 frameshift
NM_006236.3 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 4.38
Genes affected
POU3F3 (HGNC:9216): (POU class 3 homeobox 3) This gene encodes a POU-domain containing protein that functions as a transcription factor. The encoded protein recognizes an octamer sequence in the DNA of target genes. This protein may play a role in development of the nervous system. [provided by RefSeq, Apr 2015]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 8 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 15 pathogenic variants in the truncated region.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 2-104856706-AG-A is Pathogenic according to our data. Variant chr2-104856706-AG-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 521216.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-104856706-AG-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
POU3F3 | NM_006236.3 | c.1197del | p.Ile400SerfsTer16 | frameshift_variant | 1/1 | ENST00000361360.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
POU3F3 | ENST00000361360.4 | c.1197del | p.Ile400SerfsTer16 | frameshift_variant | 1/1 | NM_006236.3 | P1 | ||
ENST00000662784.1 | n.166+2875del | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes ? Cov.: 31
GnomAD3 genomes
?
Cov.:
31
GnomAD4 exome Cov.: 37
GnomAD4 exome
Cov.:
37
GnomAD4 genome ? Cov.: 31
GnomAD4 genome
?
Cov.:
31
ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Inborn genetic diseases Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 13, 2020 | The alteration results in a premature stop codon: _x000D_ _x000D_ The c.1197delG (p.I400Sfs*16) alteration, located in coding exon 1 of the POU3F3 gene, consists of a deletion of one nucleotide at position 1197, causing a translational frameshift with a predicted alternate stop codon after 16 amino acids. Frameshifts are typically deleterious in nature; however, because POU3F3 is a single-exon gene this alteration is not expected to trigger nonsense-mediated mRNA decay and an altered protein could still be expressed (Maquat, 2004). This alteration impacts the last 101 amino acids of the protein and this region contains the C-terminal POU-homeobox domain, which is required for sequence specific DNA binding (Rosenfeld, 1991) and in vitro studies have shown that this alteration results in abnormal subcellular localization, significantly decreased transcriptional activation function, and significantly decreased dimerization (Snijders Blok, 2019). The alteration is not observed in population databases: _x000D_ _x000D_ Based on data from the Genome Aggregation Database (gnomAD), the POU3F3 c.1197delG alteration was not observed, with coverage at this position. Based on the available evidence, this alteration is classified as likely pathogenic. - |
Computational scores
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Calibrated prediction
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Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at