rs1131692261
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PM5PP2PP3PP5_Very_Strong
The NM_001375380.1(EBF3):c.626G>A(p.Arg209Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R209W) has been classified as Likely pathogenic.
Frequency
Consequence
NM_001375380.1 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
EBF3 | NM_001375380.1 | c.626G>A | p.Arg209Gln | missense_variant | 7/17 | ENST00000440978.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
EBF3 | ENST00000440978.2 | c.626G>A | p.Arg209Gln | missense_variant | 7/17 | 3 | NM_001375380.1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1461410Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0AN XY: 726996
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratoire de Génétique Moléculaire, CHU Bordeaux | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 11, 2022 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28017373, 33102976, 29162653) - |
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 11, 2024 | The c.626G>A (p.R209Q) alteration is located in coding exon 7 of the EBF3 gene. This alteration results from a G to A substitution at nucleotide position 626, causing the arginine (R) at amino acid position 209 to be replaced by a glutamine (Q). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been determined to be the result of a de novo mutation in multiple individuals with features consistent with EBF3-related neurodevelopmental disorder (Tanaka, 2017; DECIPHER v.9.32; Ambry internal data). Another alteration at the same codon, c.625C>T (p.R209W), has been detected as de novo and mosaic in the mother in related individuals with intellectual disability, developmental delay, ataxia, seizures, and dysmorphic features (Harms, 2017). This amino acid position is highly conserved in available vertebrate species. This missense alteration is located in a region that has a low rate of benign missense variation (Lek, 2016; Firth, 2009). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. - |
Hypotonia, ataxia, and delayed development syndrome Other:1
not provided, no classification provided | literature only | GeneReviews | - | Reported in 2 unrelated persons - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at