rs1555767285
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 22 ACMG points: 22P and 0B. PVS1PM2PP3_StrongPP5_Very_Strong
The NM_000709.4(BCKDHA):c.1168-2A>G variant causes a splice acceptor change. The variant allele was found at a frequency of 0.00000205 in 1,461,660 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 Likely pathogenic (★★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000021 ( 0 hom. )
Consequence
BCKDHA
NM_000709.4 splice_acceptor
NM_000709.4 splice_acceptor
Scores
4
2
1
Splicing: ADA: 1.000
2
Clinical Significance
Conservation
PhyloP100: 6.35
Genes affected
BCKDHA (HGNC:986): (branched chain keto acid dehydrogenase E1 subunit alpha) The branched-chain alpha-keto acid (BCAA) dehydrogenase (BCKD) complex is an innter mitochondrial enzyme complex that catalyzes the second major step in the catabolism of the branched-chain amino acids leucine, isoleucine, and valine. The BCKD complex consists of three catalytic components: a heterotetrameric (alpha2-beta2) branched-chain alpha-keto acid decarboxylase (E1), a dihydrolipoyl transacylase (E2), and a dihydrolipoamide dehydrogenase (E3). This gene encodes the alpha subunit of the decarboxylase (E1) component. Mutations in this gene result in maple syrup urine disease, type IA. Multiple transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Sep 2009]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 22 ACMG points.
PVS1
?
Splicing variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
?
Variant 19-41424436-A-G is Pathogenic according to our data. Variant chr19-41424436-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 431986.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BCKDHA | NM_000709.4 | c.1168-2A>G | splice_acceptor_variant | ENST00000269980.7 | |||
BCKDHA | NM_001164783.2 | c.1165-2A>G | splice_acceptor_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BCKDHA | ENST00000269980.7 | c.1168-2A>G | splice_acceptor_variant | 1 | NM_000709.4 | P1 | |||
BCKDHA | ENST00000457836.6 | c.1177-2A>G | splice_acceptor_variant | 2 | |||||
BCKDHA | ENST00000544905.1 | c.62-66A>G | intron_variant | 2 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461660Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1AN XY: 727144
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727144
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GnomAD4 genome ? Cov.: 32
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32
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Maple syrup urine disease Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | May 06, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jul 25, 2023 | For these reasons, this variant has been classified as Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 431986). This variant is also known as IVS8-2A>G. Disruption of this splice site has been observed in individual(s) with maple syrup urine disease (PMID: 19480318, 31980395; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 8 of the BCKDHA gene. While this variant is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Aug 22, 2017 | - - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 06, 2017 | The c.1168-2 A>G variant was identified in a patient with classic MSUD who was homozygous for c.1168-2 A>G (Gorzelany et al. 2009). The c.1168-2 A>G variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The c.1168-2 A>G variant destroys the canonical splice acceptor site in intron 8 and is predicted to result in an in-frame deletion of a critical region. In summary, this variant is likely pathogenic. - |
Maple syrup urine disease type 1A Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 03, 2017 | Variant summary: The BCKDHA c.1168-2A>G variant involves the alteration of a conserved intronic nucleotide and 3/5 splice prediction tools predict significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. This variant was found in 1/120930 control chromosomes at a frequency of 0.0000083, which does not exceed the estimated maximal expected allele frequency of a pathogenic BCKDHA variant (0.0016771). A publication cites the variant occurring in a homozygous individual presenting with classic maple syrup urine disease. Taken together, this variant is classified as likely pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
D;D
GERP RS
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_AL_spliceai
Position offset: 2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at