rs45500792

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The 19-41397794-T-G variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.133 in 1,605,510 control chromosomes in the GnomAD database, including 15,174 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.10 ( 907 hom., cov: 33)

Exomes 𝑓: 0.14 ( 14267 hom. )

Consequence

BCKDHA
NM_000709.4 upstream_gene

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.433

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 Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.97).

BP6

Variant 19-41397794-T-G is Benign according to our data. Variant chr19-41397794-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 93334.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.148 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BCKDHA	NM_000709.4 linkuse as main transcript			upstream_gene_variant		ENST00000269980.7
BCKDHA	NM_001164783.2 linkuse as main transcript			upstream_gene_variant

Ensembl

Gene	Transcript	Effect	TSL	MANE	Appris	UniProt
BCKDHA	ENST00000269980.7 linkuse as main transcript	upstream_gene_variant	1	NM_000709.4	P1	P12694-1
BCKDHA	ENST00000457836.6 linkuse as main transcript	upstream_gene_variant	2			P12694-2
BCKDHA	ENST00000542943.5 linkuse as main transcript	upstream_gene_variant	5
BCKDHA	ENST00000538423.5 linkuse as main transcript	upstream_gene_variant	5

Frequencies

GnomAD3 genomes

AF:

0.102

AC:

15471

AN:

152214

Hom.:

908

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0382

Gnomad AMI

AF:

0.156

Gnomad AMR

AF:

0.106

Gnomad ASJ

AF:

0.142

Gnomad EAS

AF:

0.0468

Gnomad SAS

AF:

0.157

Gnomad FIN

AF:

0.0937

Gnomad MID

AF:

0.127

Gnomad NFE

AF:

0.138

Gnomad OTH

AF:

0.100

GnomAD3 exomes

AF:

0.115

AC:

28721

AN:

249866

Hom.:

1867

AF XY:

0.121

AC XY:

16352

AN XY:

135206

show subpopulations

Gnomad AFR exome

AF:

0.0366

Gnomad AMR exome

AF:

0.0674

Gnomad ASJ exome

AF:

0.136

Gnomad EAS exome

AF:

0.0528

Gnomad SAS exome

AF:

0.161

Gnomad FIN exome

AF:

0.0966

Gnomad NFE exome

AF:

0.139

Gnomad OTH exome

AF:

0.124

GnomAD4 exome

AF:

0.136

AC:

197327

AN:

1453178

Hom.:

14267

Cov.:

AF XY:

0.137

AC XY:

99142

AN XY:

723392

show subpopulations

Gnomad4 AFR exome

AF:

0.0365

Gnomad4 AMR exome

AF:

0.0713

Gnomad4 ASJ exome

AF:

0.133

Gnomad4 EAS exome

AF:

0.0498

Gnomad4 SAS exome

AF:

0.158

Gnomad4 FIN exome

AF:

0.0973

Gnomad4 NFE exome

AF:

0.145

Gnomad4 OTH exome

AF:

0.133

GnomAD4 genome

AF:

0.102

AC:

15470

AN:

152332

Hom.:

907

Cov.:

AF XY:

0.100

AC XY:

7455

AN XY:

74484

show subpopulations

Gnomad4 AFR

AF:

0.0382

Gnomad4 AMR

AF:

0.106

Gnomad4 ASJ

AF:

0.142

Gnomad4 EAS

AF:

0.0463

Gnomad4 SAS

AF:

0.157

Gnomad4 FIN

AF:

0.0937

Gnomad4 NFE

AF:

0.138

Gnomad4 OTH

AF:

0.101

Alfa

AF:

0.131

Hom.:

808

Bravo

AF:

0.0983

Asia WGS

AF:

0.100

AC:

346

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Maple syrup urine disease

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

BCKDHA-related disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 21, 2021

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.97

Cadd

Benign

0.93

Dann

Benign

0.50

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