rs398123496
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1_StrongPM2PP3_StrongPP5_Very_Strong
The NM_000709.4(BCKDHA):c.288+1G>A variant causes a splice donor change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000752 in 1,461,860 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/2 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Consequence
NM_000709.4 splice_donor
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BCKDHA | NM_000709.4 | c.288+1G>A | splice_donor_variant | ENST00000269980.7 | |||
BCKDHA | NM_001164783.2 | c.288+1G>A | splice_donor_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BCKDHA | ENST00000269980.7 | c.288+1G>A | splice_donor_variant | 1 | NM_000709.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251274Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135846
GnomAD4 exome AF: 0.00000752 AC: 11AN: 1461860Hom.: 0 Cov.: 33 AF XY: 0.00000413 AC XY: 3AN XY: 727238
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Maple syrup urine disease Pathogenic:6
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 24, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Nov 10, 2021 | NM_000709.3(BCKDHA):c.288+1G>A is a canonical splice variant classified as pathogenic in the context of maple syrup urine disease type Ia. c.288+1G>A has been observed in cases with relevant disease (PMID: 31980395, 31119508). Functional assessments of this variant are not available in the literature. c.288+1G>A has been observed in population frequency databases (gnomAD: OTH 0.02%). In summary, NM_000709.3(BCKDHA):c.288+1G>A is a canonical splice variant that has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Feb 18, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Nov 07, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 19, 2023 | This sequence change affects a donor splice site in intron 2 of the BCKDHA gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in BCKDHA are known to be pathogenic (PMID: 16786533, 22593002). This variant is present in population databases (rs398123496, gnomAD 0.006%). Disruption of this splice site has been observed in individual(s) with maple syrup urine disease (PMID: 26901124). ClinVar contains an entry for this variant (Variation ID: 93351). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | National Newborn Screening Laboratory, Hospital Nacional de Niños | - | This variant is located within the ±2 bp from a splice site in the BCKDHA gene, where loss of function is a known mechanism of disease. It is present in population databases in low frequency (GnomAD exomes: 0.000016, ExAC: A=0.000008). This variant has been published in the literature associated with individuals with MSUD (PMID: 26901124, PMID: 31119508). It was found in a compound heterozygous state with a pathogenic variant in a patient with MSUD phenotype. - |
Maple syrup urine disease type 1A Pathogenic:2
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 19, 2021 | Variant summary: BCKDHA c.288+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5 splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 1.6e-05 in 251274 control chromosomes (gnomAD). c.288+1G>A has been reported in the literature in at least a homozygous individual affected with Maple Syrup Urine Disease (example: Abiri_BCKDHA_MutatRes_2016, Strauss_BCKDHA_MGM_2020). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submitters (evaluation after 2014) cite the variant as likely pathogenic/pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Aug 23, 2013 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 23, 2015 | The c.288+1 G>A splice site mutation in the BCKDHA gene destroys the canonical splice donor site in intron 2. It is predicted to cause abnormal gene splicing, either leading to an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. The variant is found in BCKDHA panel(s). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at