7-2539812-C-G
Variant summary
Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong
The NM_152743.4(BRAT1):c.1472G>C(p.Gly491Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000745 in 1,611,746 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. 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. G491S) 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: Likely_benign. The variant received -4 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes  0.0000131  AC: 2AN: 152204Hom.:  0  Cov.: 33 show subpopulations 
GnomAD2 exomes  AF:  0.0000452  AC: 11AN: 243096 AF XY:  0.0000303   show subpopulations 
GnomAD4 exome  AF:  0.00000685  AC: 10AN: 1459542Hom.:  0  Cov.: 32 AF XY:  0.00000551  AC XY: 4AN XY: 725936 show subpopulations 
Age Distribution
GnomAD4 genome  0.0000131  AC: 2AN: 152204Hom.:  0  Cov.: 33 AF XY:  0.0000135  AC XY: 1AN XY: 74344 show subpopulations 
Age Distribution
ClinVar
Submissions by phenotype
Neonatal-onset encephalopathy with rigidity and seizures    Uncertain:1 
This sequence change replaces glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 491 of the BRAT1 protein (p.Gly491Ala). This variant is present in population databases (rs762040027, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with BRAT1-related conditions. ClinVar contains an entry for this variant (Variation ID: 540167). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt BRAT1 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
not provided    Uncertain:1 
In silico analysis indicates that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
Computational scores
Source: 
Splicing
 Find out detailed SpliceAI scores and Pangolin per-transcript scores at