rs3213861

Positions:

Variant summary

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

The NM_000709.4(BCKDHA):c.376-10A>C variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.611 in 1,611,524 control chromosomes in the GnomAD database, including 304,273 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.66 ( 33842 hom., cov: 31)

Exomes 𝑓: 0.61 ( 270431 hom. )

Consequence

BCKDHA
NM_000709.4 splice_polypyrimidine_tract, intron

Scores

Splicing: ADA: 0.00009352

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -0.513

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=-0.71).

BP6

Variant 19-41414039-A-C is Benign according to our data. Variant chr19-41414039-A-C is described in ClinVar as [Benign]. Clinvar id is 93357.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-41414039-A-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.813 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BCKDHA	NM_000709.4 linkuse as main transcript	c.376-10A>C		splice_polypyrimidine_tract_variant, intron_variant		ENST00000269980.7
BCKDHA	NM_001164783.2 linkuse as main transcript	c.376-10A>C		splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BCKDHA	ENST00000269980.7 linkuse as main transcript	c.376-10A>C		splice_polypyrimidine_tract_variant, intron_variant		1	NM_000709.4	P1	P12694-1

Frequencies

GnomAD3 genomes

AF:

0.657

AC:

99731

AN:

151882

Hom.:

33799

Cov.:

show subpopulations

Gnomad AFR

AF:

0.821

Gnomad AMI

AF:

0.769

Gnomad AMR

AF:

0.560

Gnomad ASJ

AF:

0.625

Gnomad EAS

AF:

0.430

Gnomad SAS

AF:

0.589

Gnomad FIN

AF:

0.661

Gnomad MID

AF:

0.636

Gnomad NFE

AF:

0.601

Gnomad OTH

AF:

0.638

GnomAD3 exomes

AF:

0.591

AC:

147875

AN:

250126

Hom.:

44855

AF XY:

0.591

AC XY:

80099

AN XY:

135546

show subpopulations

Gnomad AFR exome

AF:

0.824

Gnomad AMR exome

AF:

0.478

Gnomad ASJ exome

AF:

0.626

Gnomad EAS exome

AF:

0.424

Gnomad SAS exome

AF:

0.589

Gnomad FIN exome

AF:

0.656

Gnomad NFE exome

AF:

0.604

Gnomad OTH exome

AF:

0.607

GnomAD4 exome

AF:

0.606

AC:

884403

AN:

1459524

Hom.:

270431

Cov.:

AF XY:

0.605

AC XY:

439283

AN XY:

726178

show subpopulations

Gnomad4 AFR exome

AF:

0.832

Gnomad4 AMR exome

AF:

0.485

Gnomad4 ASJ exome

AF:

0.624

Gnomad4 EAS exome

AF:

0.456

Gnomad4 SAS exome

AF:

0.584

Gnomad4 FIN exome

AF:

0.655

Gnomad4 NFE exome

AF:

0.608

Gnomad4 OTH exome

AF:

0.614

GnomAD4 genome

AF:

0.657

AC:

99827

AN:

152000

Hom.:

33842

Cov.:

AF XY:

0.654

AC XY:

48581

AN XY:

74290

show subpopulations

Gnomad4 AFR

AF:

0.821

Gnomad4 AMR

AF:

0.559

Gnomad4 ASJ

AF:

0.625

Gnomad4 EAS

AF:

0.430

Gnomad4 SAS

AF:

0.588

Gnomad4 FIN

AF:

0.661

Gnomad4 NFE

AF:

0.601

Gnomad4 OTH

AF:

0.638

Alfa

AF:

0.617

Hom.:

11411

Bravo

AF:

0.656

Asia WGS

AF:

0.536

AC:

1864

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Maple syrup urine disease

Benign:4

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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. -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not specified

Benign:3

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 12, 2016	- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Maple syrup urine disease type 1A

Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Nov 18, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.71

CADD

Benign

2.9

DANN

Benign

0.78

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000094

dbscSNV1_RF

Benign

0.066

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