rs745563920
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The NM_152743.4(BRAT1):c.1304C>T(p.Thr435Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000138 in 1,595,316 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. T435T) has been classified as Likely benign.
Frequency
Consequence
NM_152743.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BRAT1 | NM_152743.4 | c.1304C>T | p.Thr435Met | missense_variant | 9/14 | ENST00000340611.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRAT1 | ENST00000340611.9 | c.1304C>T | p.Thr435Met | missense_variant | 9/14 | 1 | NM_152743.4 | P1 | |
BRAT1 | ENST00000467558.5 | n.1586C>T | non_coding_transcript_exon_variant | 7/10 | 5 | ||||
BRAT1 | ENST00000469750.5 | n.2786C>T | non_coding_transcript_exon_variant | 7/11 | 2 | ||||
BRAT1 | ENST00000493232.5 | n.2705C>T | non_coding_transcript_exon_variant | 2/3 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000592 AC: 9AN: 152140Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000259 AC: 6AN: 232102Hom.: 0 AF XY: 0.00000785 AC XY: 1AN XY: 127340
GnomAD4 exome AF: 0.00000832 AC: 12AN: 1443058Hom.: 0 Cov.: 33 AF XY: 0.00000836 AC XY: 6AN XY: 717580
GnomAD4 genome ? AF: 0.0000657 AC: 10AN: 152258Hom.: 0 Cov.: 32 AF XY: 0.0000672 AC XY: 5AN XY: 74440
ClinVar
Submissions by phenotype
Neonatal-onset encephalopathy with rigidity and seizures Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Nov 01, 2022 | This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 435 of the BRAT1 protein (p.Thr435Met). This variant is present in population databases (rs745563920, gnomAD 0.02%). 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: 578990). 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. - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 16, 2021 | The c.1304C>T (p.T435M) alteration is located in exon 9 (coding exon 8) of the BRAT1 gene. This alteration results from a C to T substitution at nucleotide position 1304, causing the threonine (T) at amino acid position 435 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Aug 19, 2022 | In silico analysis supports 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