rs137852875

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_000709.4(BCKDHA):c.929C>G(p.Thr310Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000434 in 1,614,062 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 (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

BCKDHA
NM_000709.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 7.37

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]

BCKDHA links:

ENSG00000255730 (HGNC:):

ENSG00000255730 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.991

PP5

Variant 19-41422704-C-G is Pathogenic according to our data. Variant chr19-41422704-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2381.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BCKDHA	NM_000709.4 linkuse as main transcript	c.929C>G	p.Thr310Arg	missense_variant	7/9	ENST00000269980.7	NP_000700.1	P12694-1A0A024R0K3
BCKDHA	NM_001164783.2 linkuse as main transcript	c.926C>G	p.Thr309Arg	missense_variant	7/9		NP_001158255.1	P12694Q59EI3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BCKDHA	ENST00000269980.7 linkuse as main transcript	c.929C>G	p.Thr310Arg	missense_variant	7/9	1	NM_000709.4	ENSP00000269980.2		P12694-1
ENSG00000255730	ENST00000540732.3 linkuse as main transcript	c.1031C>G	p.Thr344Arg	missense_variant	8/10	2		ENSP00000443246.1		F5H5P2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152214

Hom.:

Cov.:

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:

0.00

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:

AN:

251382

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135876

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000410

AC:

AN:

1461848

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727228

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000540

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152214

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74360

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Maple syrup urine disease

Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	May 22, 1998	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 30, 2022	Variant summary: BCKDHA c.929C>G (p.Thr310Arg) results in a non-conservative amino acid change located in the Dehydrogenase, E1 component domain (IPR001017) of the encoded protein sequence. This variant, located in the helix 11 region of a hydrophobic core is thought to be disrupted by the large and charged side chain of the Arg residue (AEvarrson_2000). Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251382 control chromosomes. c.929C>G has been reported in the literature as a compound heterozygous genotype in at-least one individual affected with Maple Syrup Urine Disease (example, Wynn_1998 cited by others). At least one publication reports experimental evidence evaluating an impact on protein function (example, Wynn_1998). The most pronounced variant effect results in non-detectable E1 Decarboxylase component enzyme activity of branched-chain ketoacid dehydrogenase complex in-vitro due to an adverse impact on E1-alpha folding and subunit interactions. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. 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 25, 2013	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 07, 2024	Published functional studies demonstrate that p.(T310R) decreased thermal stability and E1 catalytic activity in vitro (PMID: 9582350); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as T265R; This variant is associated with the following publications: (PMID: 9609836, 9582350, 10745006, 18378174, 33088714) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.57

BayesDel_noAF

Pathogenic

0.58

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.83

.;D;.;.

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.93

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.99

D;D;D;D

M_CAP

Pathogenic

0.89

MetaRNN

Pathogenic

0.99

D;D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

4.1

.;H;.;.

PrimateAI

Pathogenic

0.86

PROVEAN

Pathogenic

-5.3

D;D;D;D

REVEL

Pathogenic

0.99

Sift

Uncertain

0.0010

D;D;D;D

Sift4G

Uncertain

0.0030

D;D;D;D

Polyphen

1.0

.;D;.;.

Vest4

0.97

MutPred

0.93

Gain of methylation at T344 (P = 0.0173);.;.;.;

MVP

0.95

MPC

2.0

ClinPred

1.0

GERP RS

5.7

Varity_R

0.99

gMVP

0.96

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over