rs4674

chr19-41424491-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000709.4(BCKDHA):c.1221A>G(p.Leu407=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.612 in 1,613,672 control chromosomes in the GnomAD database, including 305,356 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.66 (33918 hom., cov: 31)
  • Exomes 𝑓: 0.61 (271438 hom.)
• Consequence: BCKDHA NM_000709.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.759

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).
• BP6: Variant 19-41424491-A-G is Benign according to our data. Variant chr19-41424491-A-G is described in ClinVar as [Benign]. Clinvar id is 93343.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-41424491-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.759 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.814 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BCKDHA	NM_000709.4	c.1221A>G	p.Leu407=	synonymous_variant	9/9	ENST00000269980.7
BCKDHA	NM_001164783.2	c.1218A>G	p.Leu406=	synonymous_variant	9/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BCKDHA	ENST00000269980.7	c.1221A>G	p.Leu407=	synonymous_variant	9/9	1	NM_000709.4	P1
BCKDHA	ENST00000457836.6	c.1230A>G	p.Leu410=	synonymous_variant	9/9	2
BCKDHA	ENST00000544905.1	c.62-11A>G		splice_polypyrimidine_tract_variant, intron_variant		2

Frequencies

GnomAD3 genomes AF: 0.658 AC: 99862 AN: 151750 Hom.: 33876 Cov.: 31

Gnomad AFR AF: 0.822

Gnomad AMI AF: 0.772

Gnomad AMR AF: 0.561

Gnomad ASJ AF: 0.627

Gnomad EAS AF: 0.437

Gnomad SAS AF: 0.589

Gnomad FIN AF: 0.663

Gnomad MID AF: 0.639

Gnomad NFE AF: 0.602

Gnomad OTH AF: 0.639

GnomAD3 exomes AF: 0.592 AC: 147600 AN: 249152 Hom.: 44860 AF XY: 0.592 AC XY: 79805 AN XY: 134868

Gnomad AFR exome AF: 0.825

Gnomad AMR exome AF: 0.479

Gnomad ASJ exome AF: 0.626

Gnomad EAS exome AF: 0.431

Gnomad SAS exome AF: 0.588

Gnomad FIN exome AF: 0.656

Gnomad NFE exome AF: 0.605

Gnomad OTH exome AF: 0.608

GnomAD4 exome AF: 0.607 AC: 886891 AN: 1461804 Hom.: 271438 Cov.: 70 AF XY: 0.606 AC XY: 440439 AN XY: 727208

Gnomad4 AFR exome AF: 0.833

Gnomad4 AMR exome AF: 0.485

Gnomad4 ASJ exome AF: 0.625

Gnomad4 EAS exome AF: 0.465

Gnomad4 SAS exome AF: 0.583

Gnomad4 FIN exome AF: 0.655

Gnomad4 NFE exome AF: 0.608

Gnomad4 OTH exome AF: 0.615

GnomAD4 genome AF: 0.658 AC: 99957 AN: 151868 Hom.: 33918 Cov.: 31 AF XY: 0.655 AC XY: 48630 AN XY: 74198

Gnomad4 AFR AF: 0.822

Gnomad4 AMR AF: 0.561

Gnomad4 ASJ AF: 0.627

Gnomad4 EAS AF: 0.438

Gnomad4 SAS AF: 0.588

Gnomad4 FIN AF: 0.663

Gnomad4 NFE AF: 0.602

Gnomad4 OTH AF: 0.639

Alfa AF: 0.617 Hom.: 39667

Bravo AF: 0.658

Asia WGS AF: 0.538 AC: 1869 AN: 3478

EpiCase AF: 0.598

EpiControl AF: 0.604

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 17, 2014	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Maple syrup urine disease Benign:4

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

Maple syrup urine disease type 1A Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Nov 18, 2019

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
Cadd	Benign	8.0
Dann	Benign	0.79

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

Other links and lift over

dbSNP: rs4674; hg19: chr19-41930396; COSMIC: COSV54195656; COSMIC: COSV54195656;