chr7-2540996-G-C
Variant summary
Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2
The NM_152743.4(BRAT1):c.1378C>G(p.Pro460Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P460L) has been classified as Uncertain significance.
Frequency
Consequence
NM_152743.4 missense
Scores
Clinical Significance
Conservation
Publications
- neonatal-onset encephalopathy with rigidity and seizuresInheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, ClinGen, G2P, Labcorp Genetics (formerly Invitae)
- neurodevelopmental disorder with cerebellar atrophy and with or without seizuresInheritance: AR Classification: DEFINITIVE Submitted by: ClinGen, Ambry Genetics
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ACMG classification
Our verdict: Uncertain_significance. The variant received 2 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD2 exomes AF: 0.00 AC: 0AN: 186618 AF XY: 0.00
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1400966Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 696056
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Neonatal-onset encephalopathy with rigidity and seizures Uncertain:1
This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a BRAT1-related disease. This sequence change replaces proline with alanine at codon 460 of the BRAT1 protein (p.Pro460Ala). The proline residue is highly conserved and there is a small physicochemical difference between proline and alanine. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at