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rs1553426462

Positions:

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

Scores

Not classified

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 8.60
Variant links:
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
?
    PM1 - Located in a mutational hot spot and/or critical and well-established functional domain (e.g., active site of an enzyme) without benign variation
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
?
    PM2 - Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium
Very rare variant in population databases, with high coverage;
PM4
?
    PM4 - Protein length changes as a result of in-frame deletions/insertions in a nonrepeat region or stop-loss variants
Nonframeshift variant in NON repetitive region in NM_006236.3.
PP3
?
    PP3 - Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.)
No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
PP5
?
    PP5 - Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation
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
POU3F3NM_006236.3 linkuse as main transcriptc.992_1006del p.Gln331_Lys335del inframe_deletion 1/1 ENST00000361360.4

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
POU3F3ENST00000361360.4 linkuse as main transcriptc.992_1006del p.Gln331_Lys335del inframe_deletion 1/1 NM_006236.3 P1
ENST00000662784.1 linkuse as main transcriptn.166+2670_166+2684del intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
Cov.:
32
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
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 submitterclinical testingAmbry GeneticsFeb 19, 2020The 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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1553426462; hg19: chr2-105472953; API