rs398123486

Positions:

chr19-41423039-G-A

Variant summary

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

The NM_000709.4(BCKDHA):c.1037G>A(p.Arg346His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000374 in 1,606,188 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000028 ( 0 hom. )

Consequence

BCKDHA
NM_000709.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5U:1

Conservation

PhyloP100: 9.07

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:

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, 0.992

PP5

Variant 19-41423039-G-A is Pathogenic according to our data. Variant chr19-41423039-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 93336.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.1037G>A	p.Arg346His	missense_variant	8/9	ENST00000269980.7	NP_000700.1
BCKDHA	NM_001164783.2 linkuse as main transcript	c.1034G>A	p.Arg345His	missense_variant	8/9		NP_001158255.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BCKDHA	ENST00000269980.7 linkuse as main transcript	c.1037G>A	p.Arg346His	missense_variant	8/9	1	NM_000709.4	ENSP00000269980	P1	P12694-1
BCKDHA	ENST00000457836.6 linkuse as main transcript	c.1046G>A	p.Arg349His	missense_variant	8/9	2		ENSP00000416000		P12694-2
BCKDHA	ENST00000542943.5 linkuse as main transcript	c.950G>A	p.Arg317His	missense_variant	7/7	5		ENSP00000440345

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152128

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.00

Gnomad OTH

AF:

0.000478

GnomAD4 exome

AF:

0.00000275

AC:

AN:

1454060

Hom.:

Cov.:

AF XY:

0.00000415

AC XY:

AN XY:

722526

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:

0.0000118

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152128

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74310

show subpopulations

Gnomad4 AFR

AF:

0.0000241

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:

0.00

Gnomad4 OTH

AF:

0.000478

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Maple syrup urine disease

Pathogenic:3Uncertain:1

Likely pathogenic, no assertion criteria provided	research	Shieh Lab, University of California, San Francisco	Oct 19, 2020	- -
Uncertain significance, no assertion criteria provided	clinical testing	Counsyl	Jul 05, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 07, 2023	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. For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg346 amino acid residue in BCKDHA. Other variant(s) that disrupt this residue have been observed in individuals with BCKDHA-related conditions (PMID: 16786533, 21844576, 22593002), which suggests that this may be a clinically significant amino acid residue. ClinVar contains an entry for this variant (Variation ID: 93336). This missense change has been observed in individual(s) with BCKDHA-related conditions (PMID: 16786533). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 346 of the BCKDHA protein (p.Arg346His). -
Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Nov 29, 2021	- -

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jun 14, 2017

- -

Maple syrup urine disease type 1A

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Nov 22, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.58

BayesDel_noAF

Pathogenic

0.60

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.87

.;D;.;.

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.90

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

1.0

D;D;D;D

M_CAP

Pathogenic

0.82

MetaRNN

Pathogenic

0.99

D;D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

4.8

.;H;.;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.79

PROVEAN

Pathogenic

-4.9

D;D;D;D

REVEL

Pathogenic

0.96

Sift

Pathogenic

0.0

D;D;D;D

Sift4G

Pathogenic

0.0010

D;D;D;D

Polyphen

1.0

.;D;.;.

Vest4

0.93

MutPred

0.93

Loss of stability (P = 0.0899);.;.;.;

MVP

0.98

MPC

2.1

ClinPred

1.0

GERP RS

5.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.94

gMVP

0.86

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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