19-41422634-C-G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP3_StrongPP5

The NM_000709.4(BCKDHA):ā€‹c.859C>Gā€‹(p.Arg287Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000991 in 1,613,942 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: š‘“ 0.000013 ( 0 hom., cov: 32)
Exomes š‘“: 0.0000096 ( 0 hom. )

Consequence

BCKDHA
NM_000709.4 missense

Scores

16
2
1

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:1

Conservation

PhyloP100: 2.62
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.951
PP5
Variant 19-41422634-C-G is Pathogenic according to our data. Variant chr19-41422634-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1334170.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=1}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
BCKDHANM_000709.4 linkuse as main transcriptc.859C>G p.Arg287Gly missense_variant 7/9 ENST00000269980.7 NP_000700.1
BCKDHANM_001164783.2 linkuse as main transcriptc.856C>G p.Arg286Gly missense_variant, splice_region_variant 7/9 NP_001158255.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
BCKDHAENST00000269980.7 linkuse as main transcriptc.859C>G p.Arg287Gly missense_variant 7/91 NM_000709.4 ENSP00000269980 P1P12694-1

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152150
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000193
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000796
AC:
2
AN:
251376
Hom.:
0
AF XY:
0.00000736
AC XY:
1
AN XY:
135880
show subpopulations
Gnomad AFR exome
AF:
0.0000615
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000544
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000958
AC:
14
AN:
1461792
Hom.:
0
Cov.:
33
AF XY:
0.0000124
AC XY:
9
AN XY:
727206
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000756
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000719
Gnomad4 OTH exome
AF:
0.0000331
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152150
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74330
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000193
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000425
Hom.:
0
Bravo
AF:
0.00000756
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:2Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Maple syrup urine disease Pathogenic:1Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingMyriad Genetics, Inc.Nov 15, 2021NM_000709.3(BCKDHA):c.859C>G(R287G) is a missense variant classified as a variant of uncertain significance in the context of maple syrup urine disease type Ia. R287G has been observed in a case with relevant disease (PMID: 32193832). Functional assessments of this variant are not available in the literature. R287G has been observed in population frequency databases (gnomAD: AFR 0.01%). In summary, there is insufficient evidence to classify NM_000709.3(BCKDHA):c.859C>G(R287G) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening. -
Likely pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpNov 19, 2023This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 287 of the BCKDHA protein (p.Arg287Gly). This variant is present in population databases (rs764247545, gnomAD 0.005%). This missense change has been observed in individual(s) with maple syrup urine disease (PMID: 32193832). ClinVar contains an entry for this variant (Variation ID: 1334170). 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 expected to disrupt BCKDHA protein function with a positive predictive value of 95%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -
Maple syrup urine disease type 1A Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingBaylor GeneticsFeb 17, 2024- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.42
D
BayesDel_noAF
Pathogenic
0.55
CADD
Pathogenic
29
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.86
.;D;.;.
Eigen
Pathogenic
0.91
Eigen_PC
Pathogenic
0.79
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Pathogenic
0.99
D;D;D;D
M_CAP
Pathogenic
0.88
D
MetaRNN
Pathogenic
0.95
D;D;D;D
MetaSVM
Pathogenic
0.97
D
MutationAssessor
Pathogenic
4.5
.;H;.;.
MutationTaster
Benign
1.0
D;D
PrimateAI
Pathogenic
0.84
D
PROVEAN
Pathogenic
-6.5
D;D;D;D
REVEL
Pathogenic
0.92
Sift
Pathogenic
0.0
D;D;D;D
Sift4G
Pathogenic
0.0010
D;D;D;D
Polyphen
1.0
.;D;.;.
Vest4
0.91
MutPred
0.76
Loss of methylation at R321 (P = 0.0116);.;.;.;
MVP
0.94
MPC
2.1
ClinPred
1.0
D
GERP RS
4.6
Varity_R
0.97
gMVP
0.93

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.070
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs764247545; hg19: chr19-41928539; API