rs34541442

chr19-41397861-C-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000709.4(BCKDHA):c.34C>A(p.Arg12=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0123 in 1,614,172 control chromosomes in the GnomAD database, including 165 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0088 (9 hom., cov: 32)
  • Exomes 𝑓: 0.013 (156 hom.)
• Consequence: BCKDHA NM_000709.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.0490

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=-0.84).
• BP6: Variant 19-41397861-C-A is Benign according to our data. Variant chr19-41397861-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 93355.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-41397861-C-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.049 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0088 (1340/152340) while in subpopulation NFE AF= 0.0146 (993/68034). AF 95% confidence interval is 0.0138. There are 9 homozygotes in gnomad4. There are 598 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BCKDHA	NM_000709.4	c.34C>A	p.Arg12=	synonymous_variant	1/9	ENST00000269980.7
BCKDHA	NM_001164783.2	c.34C>A	p.Arg12=	synonymous_variant	1/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BCKDHA	ENST00000269980.7	c.34C>A	p.Arg12=	synonymous_variant	1/9	1	NM_000709.4	P1
BCKDHA	ENST00000457836.6	c.34C>A	p.Arg12=	synonymous_variant	1/9	2
BCKDHA	ENST00000542943.5	c.34C>A	p.Arg12=	synonymous_variant	1/7	5
BCKDHA	ENST00000538423.5	n.54C>A		non_coding_transcript_exon_variant	1/5	5

Frequencies

GnomAD3 genomes AF: 0.00880 AC: 1339 AN: 152222 Hom.: 9 Cov.: 32

Gnomad AFR AF: 0.00239

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00707

Gnomad ASJ AF: 0.0184

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00579

Gnomad FIN AF: 0.00254

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0146

Gnomad OTH AF: 0.00860

GnomAD3 exomes AF: 0.0102 AC: 2560 AN: 250990 Hom.: 20 AF XY: 0.0104 AC XY: 1408 AN XY: 135806

Gnomad AFR exome AF: 0.00266

Gnomad AMR exome AF: 0.00538

Gnomad ASJ exome AF: 0.0174

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00849

Gnomad FIN exome AF: 0.00315

Gnomad NFE exome AF: 0.0157

Gnomad OTH exome AF: 0.00832

GnomAD4 exome AF: 0.0126 AC: 18478 AN: 1461832 Hom.: 156 Cov.: 32 AF XY: 0.0126 AC XY: 9141 AN XY: 727210

Gnomad4 AFR exome AF: 0.00188

Gnomad4 AMR exome AF: 0.00575

Gnomad4 ASJ exome AF: 0.0159

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00859

Gnomad4 FIN exome AF: 0.00307

Gnomad4 NFE exome AF: 0.0145

Gnomad4 OTH exome AF: 0.0108

GnomAD4 genome AF: 0.00880 AC: 1340 AN: 152340 Hom.: 9 Cov.: 32 AF XY: 0.00803 AC XY: 598 AN XY: 74486

Gnomad4 AFR AF: 0.00238

Gnomad4 AMR AF: 0.00707

Gnomad4 ASJ AF: 0.0184

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00601

Gnomad4 FIN AF: 0.00254

Gnomad4 NFE AF: 0.0146

Gnomad4 OTH AF: 0.00851

Alfa AF: 0.0123 Hom.: 7

Bravo AF: 0.00875

Asia WGS AF: 0.00375 AC: 13 AN: 3478

EpiCase AF: 0.0155

EpiControl AF: 0.0143

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 06, 2013	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 31, 2014	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Maple syrup urine disease Benign:3

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. -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Nov 16, 2021	- -

Maple syrup urine disease type 1A Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
Cadd	Benign	5.4
Dann	Benign	0.73
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs34541442; hg19: chr19-41903766;