chr2-104856495-TTCAAGCAGCGGCGCA-T
Position:
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PM4PP3PP5_Moderate
The NM_006236.3(POU3F3):c.992_1006del(p.Gln331_Lys335del) variant causes a inframe deletion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★).
Frequency
Genomes: not found (cov: 32)
Consequence
POU3F3
NM_006236.3 inframe_deletion
NM_006236.3 inframe_deletion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 8.60
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 9 ACMG points.
PM1
In a domain POU-specific (size 74) in uniprot entity PO3F3_HUMAN there are 12 pathogenic changes around while only 0 benign (100%) in NM_006236.3
PM2
Very rare variant in population databases, with high coverage;
PM4
Nonframeshift variant in NON repetitive region in NM_006236.3.
PP3
No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
PP5
Variant 2-104856495-TTCAAGCAGCGGCGCA-T is Pathogenic according to our data. Variant chr2-104856495-TTCAAGCAGCGGCGCA-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 520803.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-104856495-TTCAAGCAGCGGCGCA-T is described in Lovd as [Pathogenic]. Variant chr2-104856495-TTCAAGCAGCGGCGCA-T is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
POU3F3 | NM_006236.3 | c.992_1006del | p.Gln331_Lys335del | inframe_deletion | 1/1 | ENST00000361360.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
POU3F3 | ENST00000361360.4 | c.992_1006del | p.Gln331_Lys335del | inframe_deletion | 1/1 | NM_006236.3 | P1 | ||
ENST00000662784.1 | n.166+2670_166+2684del | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
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 19, 2020 | The alteration results in an in-frame deletion: _x000D_ _x000D_ The c.992_1006del15 (p.Q331_K335del) alteration, located in coding exon 1 of the POU3F3 gene, results from an in-frame deletion of 15 nucleotides at positions 992 to 1006. This results in the deletion of 5 amino acids between codons 331 and 335. The alteration is not observed in population databases: _x000D_ _x000D_ Based on data from the Genome Aggregation Database (gnomAD), the POU3F3 c.992_1006del15 alteration was not observed, with coverage at this position. The alteration has been observed in affected individuals: _x000D_ _x000D_ This alteration was confirmed de novo in a 12 year old female patient with borderline ID, delayed speech and motor development, and dysmorphic features including cupped ears, long/narrow face, full lips, and high/narrow palate (Snijders Blok, 2019). The deleted amino acids are conserved throughout evolution:_x000D_ _x000D_ The Q331_K335 amino acids are completely conserved in available vertebrate species. The alteration is predicted deleterious by in silico modeling:_x000D_ _x000D_ The p.Q331_K335del alteration is predicted to be deleterious with a score of -38.00 by PROVEAN in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at