rs753216964
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong
The NM_000709.4(BCKDHA):c.647-1G>C variant causes a splice acceptor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000868 in 1,613,108 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Consequence
NM_000709.4 splice_acceptor, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
BCKDHA | NM_000709.4 | c.647-1G>C | splice_acceptor_variant, intron_variant | ENST00000269980.7 | NP_000700.1 | |||
BCKDHA | NM_001164783.2 | c.647-1G>C | splice_acceptor_variant, intron_variant | NP_001158255.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
BCKDHA | ENST00000269980.7 | c.647-1G>C | splice_acceptor_variant, intron_variant | 1 | NM_000709.4 | ENSP00000269980.2 | ||||
ENSG00000255730 | ENST00000540732.3 | c.749-1G>C | splice_acceptor_variant, intron_variant | 2 | ENSP00000443246.1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152166Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000402 AC: 1AN: 248460Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 134674
GnomAD4 exome AF: 0.00000890 AC: 13AN: 1460942Hom.: 0 Cov.: 33 AF XY: 0.00000963 AC XY: 7AN XY: 726762
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152166Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74346
ClinVar
Submissions by phenotype
Maple syrup urine disease Pathogenic:6
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 13, 2024 | This sequence change affects an acceptor splice site in intron 5 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 (rs753216964, gnomAD 0.0009%). Disruption of this splice site has been observed in individuals with maple syrup urine disease (PMID: 19715473, 31980395). This variant is also known as IVS5-1G>C. ClinVar contains an entry for this variant (Variation ID: 431985). 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 | Revvity Omics, Revvity | Dec 21, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Nov 07, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Aug 18, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Nov 16, 2021 | NM_000709.3(BCKDHA):c.647-1G>C is a canonical splice variant classified as pathogenic in the context of maple syrup urine disease type Ia. c.647-1G>C has been observed in cases with relevant disease (PMID: 19715473, 31980395, 28417071). Functional assessments of this variant are not available in the literature. c.647-1G>C has been observed in population frequency databases (ExAC: 0.002%). In summary, NM_000709.3(BCKDHA):c.647-1G>C is a canonical splice variant that has internal structural support for pathogenicity and 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 | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 24, 2020 | Variant summary: BCKDHA c.647-1G>C 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 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4e-06 in 248460 control chromosomes. c.647-1G>C has been reported in the literature in individuals affected with Maple syrup urine disease (Strauss_2006, Georgiou_2009). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 21, 2019 | Canonical splice site variant predicted to result in an in-frame deletion of a critical region.; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 19715473, 28417071, 25525159, 29789446, 26901124, 31980395) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at