rs754828716
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_StrongPM2PP5_Moderate
The NM_152743.4(BRAT1):c.1930C>T(p.Arg644Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000188 in 1,597,352 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. R644R) has been classified as Benign.
Frequency
Consequence
NM_152743.4 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BRAT1 | NM_152743.4 | c.1930C>T | p.Arg644Ter | stop_gained | 14/14 | ENST00000340611.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRAT1 | ENST00000340611.9 | c.1930C>T | p.Arg644Ter | stop_gained | 14/14 | 1 | NM_152743.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152172Hom.: 0 Cov.: 34
GnomAD3 exomes AF: 0.00000444 AC: 1AN: 225374Hom.: 0 AF XY: 0.00000797 AC XY: 1AN XY: 125496
GnomAD4 exome AF: 0.00000138 AC: 2AN: 1445180Hom.: 0 Cov.: 69 AF XY: 0.00000278 AC XY: 2AN XY: 719384
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152172Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0AN XY: 74348
ClinVar
Submissions by phenotype
BRAT1-related neurodevelopmental disorder Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Nov 04, 2022 | This variant is classified as Likely Pathogenic. Evidence in support of pathogenic classification: - Variant is predicted to result in a truncated protein (premature termination codon is NOT located at least 54 nucleotides upstream of the final exon-exon junction) with less than 1/3 of the protein This variant is classified as Likely Pathogenic. Evidence in support of pathogenic classification: - Variant is predicted to result in a truncated protein (premature termination codon is NOT located at least 54 nucleotides upstream of the final exon-exon junction) with less than 1/3 of the protein sequence affected. - Variant is present in gnomAD (v2) <0.01 for a recessive condition (1 heterozygote, 0 homozygotes). - Other variants comparable to the one identified in this case have strong previous evidence for pathogenicity. Other downstream truncating variants have previously been reported as pathogenic in a small number of families, however some have also been classified as VUS ( ClinVar, PMIDs: 27480663, 31868227, 32345087). Additional information: - Loss of function is a known mechanism of disease in this gene and is associated with BRAT1-related neurodevelopmental disorder. - This gene is associated with autosomal recessive disease. - This variant is heterozygous. - Variant is located in the annotated heat repeat motif (NCBI). - This variant has no previous evidence of pathogenicity. - No published segregation evidence has been identified for this variant. - No published functional evidence has been identified for this variant. - This variant has been shown to be paternally inherited (by trio analysis). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at