rs34442879

Positions:

chr19-41414125-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000709.4(BCKDHA):c.452C>T(p.Thr151Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00885 in 1,613,696 control chromosomes in the GnomAD database, including 98 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0079 ( 14 hom., cov: 32)

Exomes 𝑓: 0.0090 ( 84 hom. )

Consequence

BCKDHA
NM_000709.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14

Conservation

PhyloP100: 1.31

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 Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.017781347).

BP6

Variant 19-41414125-C-T is Benign according to our data. Variant chr19-41414125-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 93361.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-41414125-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00786 (1198/152328) while in subpopulation NFE AF= 0.0103 (701/68038). AF 95% confidence interval is 0.00967. There are 14 homozygotes in gnomad4. There are 647 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 14 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BCKDHA	NM_000709.4 link	c.452C>T	p.Thr151Met	missense_variant	4/9	ENST00000269980.7	NP_000700.1	P12694-1A0A024R0K3
BCKDHA	NM_001164783.2 link	c.452C>T	p.Thr151Met	missense_variant	4/9		NP_001158255.1	P12694Q59EI3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BCKDHA	ENST00000269980.7 link	c.452C>T	p.Thr151Met	missense_variant	4/9	1	NM_000709.4	ENSP00000269980.2		P12694-1
ENSG00000255730	ENST00000540732.3 link	c.554C>T	p.Thr185Met	missense_variant	5/10	2		ENSP00000443246.1		F5H5P2

Frequencies

GnomAD3 genomes

AF:

0.00786

AC:

1197

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00150

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00510

Gnomad ASJ

AF:

0.00403

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.00414

Gnomad FIN

AF:

0.0261

Gnomad MID

AF:

0.0538

Gnomad NFE

AF:

0.0103

Gnomad OTH

AF:

0.0125

GnomAD3 exomes

AF:

0.00976

AC:

2447

AN:

250702

Hom.:

AF XY:

0.0101

AC XY:

1370

AN XY:

135732

show subpopulations

Gnomad AFR exome

AF:

0.00142

Gnomad AMR exome

AF:

0.00431

Gnomad ASJ exome

AF:

0.00498

Gnomad EAS exome

AF:

0.0000545

Gnomad SAS exome

AF:

0.00532

Gnomad FIN exome

AF:

0.0259

Gnomad NFE exome

AF:

0.0125

Gnomad OTH exome

AF:

0.0141

GnomAD4 exome

AF:

0.00895

AC:

13086

AN:

1461368

Hom.:

Cov.:

AF XY:

0.00892

AC XY:

6488

AN XY:

726988

show subpopulations

Gnomad4 AFR exome

AF:

0.00185

Gnomad4 AMR exome

AF:

0.00436

Gnomad4 ASJ exome

AF:

0.00536

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00541

Gnomad4 FIN exome

AF:

0.0251

Gnomad4 NFE exome

AF:

0.00905

Gnomad4 OTH exome

AF:

0.00926

GnomAD4 genome

AF:

0.00786

AC:

1198

AN:

152328

Hom.:

Cov.:

AF XY:

0.00869

AC XY:

647

AN XY:

74476

show subpopulations

Gnomad4 AFR

AF:

0.00149

Gnomad4 AMR

AF:

0.00510

Gnomad4 ASJ

AF:

0.00403

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.00414

Gnomad4 FIN

AF:

0.0261

Gnomad4 NFE

AF:

0.0103

Gnomad4 OTH

AF:

0.0123

Alfa

AF:

0.0103

Hom.:

Bravo

AF:

0.00627

TwinsUK

AF:

0.00944

AC:

ALSPAC

AF:

0.00571

AC:

ESP6500AA

AF:

0.00159

AC:

ESP6500EA

AF:

0.0106

AC:

ExAC

AF:

0.0106

AC:

1290

Asia WGS

AF:

0.00231

AC:

AN:

3478

EpiCase

AF:

0.0109

EpiControl

AF:

0.0120

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 26, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Sep 02, 2015	- -
Benign, criteria provided, single submitter	curation	SIB Swiss Institute of Bioinformatics	May 31, 2018	This variant is interpreted as a Benign - Stand Alone. The following ACMG Tag(s) were applied: BA1 => Allele frequency is >1% in Exome Aggregation Consortium. BCKDHA mutations are responsible for Maple syrup urine disease but it is not known if this variant has been ever seen in patients. -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Apr 18, 2016	- -

Maple syrup urine disease

Benign:4

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Likely benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Dec 18, 2015	- -
Likely benign, criteria provided, single submitter	research	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	-	The heterozygous p.Thr151Met variant, sometimes called p.Thr106Met due to a difference in cDNA numbering, in BCKDHA has been identified in a Turkish individual with maple syrup urine disease (PMID: 12118532), but has also been identified in >2% of European (Finnish) chromosomes and 9 homozygotes in ExAC (http://gnomad.broadinstitute.org/). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely benign for autosomal recessive maple syrup urine disease. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

not provided

Benign:4

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2023	BCKDHA: BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 05, 2018	This variant is associated with the following publications: (PMID: 32193832, 31119508, 26990548, 14517957, 27535533, 27884173, 12118532, 21228398, 20981092, 22995991, 25087612) -

Maple syrup urine disease type 1A

Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 14, 2023	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Jun 03, 2020	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.088

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Uncertain

-0.060

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.53

.;D;.;.

Eigen

Uncertain

0.33

Eigen_PC

Uncertain

0.30

FATHMM_MKL

Benign

0.68

LIST_S2

Uncertain

0.93

D;D;D;D

MetaRNN

Benign

0.018

T;T;T;T

MetaSVM

Pathogenic

0.80

MutationAssessor

Benign

1.8

.;L;.;.

PrimateAI

Uncertain

0.53

PROVEAN

Benign

-1.2

N;N;N;N

REVEL

Uncertain

0.43

Sift

Uncertain

0.020

D;D;D;D

Sift4G

Uncertain

0.044

D;T;T;D

Polyphen

0.96

.;D;.;.

Vest4

0.18

MPC

1.2

ClinPred

0.023

GERP RS

4.7

Varity_R

0.15

gMVP

0.70

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