rs11549936

chr19-41410644-C-Achr19-41410644-C-Gchr19-41410644-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000709.4(BCKDHA):c.116C>A(p.Pro39His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.122 in 1,614,072 control chromosomes in the GnomAD database, including 13,304 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P39R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.089 (764 hom., cov: 32)
  • Exomes 𝑓: 0.13 (12540 hom.)
• Consequence: BCKDHA NM_000709.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -1.80

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0015936196).
• BP6: Variant 19-41410644-C-A is Benign according to our data. Variant chr19-41410644-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 93341.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-41410644-C-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.13 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BCKDHA	NM_000709.4	c.116C>A	p.Pro39His	missense_variant	2/9	ENST00000269980.7
BCKDHA	NM_001164783.2	c.116C>A	p.Pro39His	missense_variant	2/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BCKDHA	ENST00000269980.7	c.116C>A	p.Pro39His	missense_variant	2/9	1	NM_000709.4	P1
BCKDHA	ENST00000542943.5	c.116C>A	p.Pro39His	missense_variant	2/7	5
BCKDHA	ENST00000457836.6	c.58-8C>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		2
BCKDHA	ENST00000538423.5	n.136C>A		non_coding_transcript_exon_variant	2/5	5

Frequencies

GnomAD3 genomes AF: 0.0890 AC: 13543 AN: 152128 Hom.: 765 Cov.: 32

Gnomad AFR AF: 0.0228

Gnomad AMI AF: 0.156

Gnomad AMR AF: 0.100

Gnomad ASJ AF: 0.137

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.103

Gnomad FIN AF: 0.0715

Gnomad MID AF: 0.101

Gnomad NFE AF: 0.132

Gnomad OTH AF: 0.0927

GnomAD3 exomes AF: 0.0988 AC: 24826 AN: 251376 Hom.: 1490 AF XY: 0.104 AC XY: 14106 AN XY: 135886

Gnomad AFR exome AF: 0.0204

Gnomad AMR exome AF: 0.0629

Gnomad ASJ exome AF: 0.132

Gnomad EAS exome AF: 0.000598

Gnomad SAS exome AF: 0.116

Gnomad FIN exome AF: 0.0741

Gnomad NFE exome AF: 0.133

Gnomad OTH exome AF: 0.107

GnomAD4 exome AF: 0.125 AC: 183247 AN: 1461826 Hom.: 12540 Cov.: 34 AF XY: 0.126 AC XY: 91343 AN XY: 727218

Gnomad4 AFR exome AF: 0.0200

Gnomad4 AMR exome AF: 0.0664

Gnomad4 ASJ exome AF: 0.128

Gnomad4 EAS exome AF: 0.000504

Gnomad4 SAS exome AF: 0.116

Gnomad4 FIN exome AF: 0.0739

Gnomad4 NFE exome AF: 0.139

Gnomad4 OTH exome AF: 0.117

GnomAD4 genome AF: 0.0889 AC: 13541 AN: 152246 Hom.: 764 Cov.: 32 AF XY: 0.0861 AC XY: 6409 AN XY: 74434

Gnomad4 AFR AF: 0.0228

Gnomad4 AMR AF: 0.100

Gnomad4 ASJ AF: 0.137

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.104

Gnomad4 FIN AF: 0.0715

Gnomad4 NFE AF: 0.132

Gnomad4 OTH AF: 0.0913

Alfa AF: 0.120 Hom.: 1906

Bravo AF: 0.0874

TwinsUK AF: 0.142 AC: 528

ALSPAC AF: 0.148 AC: 571

ESP6500AA AF: 0.0238 AC: 105

ESP6500EA AF: 0.136 AC: 1170

ExAC AF: 0.0983 AC: 11938

Asia WGS AF: 0.0430 AC: 150 AN: 3478

EpiCase AF: 0.146

EpiControl AF: 0.140

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

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	Eurofins Ntd Llc (ga)	Aug 17, 2013	- -
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	Genome-Nilou Lab	Jun 10, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Maple syrup urine disease type 1A Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Feb 08, 2017

Variant summary: The BCKDHA c.116C>A (p.Pro39His) variant involves the alteration of a non-conserved nucleotide. 3/4 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 11936/121154 control chromosomes (711 homozygotes) at a frequency of 0.0985192, which is approximately 59 times the estimated maximal expected allele frequency of a pathogenic BCKDHA variant (0.0016771), suggesting this variant is likely a benign polymorphism. This variant has been reported in multiple affected individuals who also carried other variants in BCKDHB that can explain the phenotype, and authors interpreted the variant of interest as silent variant. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign. Taken together, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.20
Cadd	Benign	0.047
Dann	Benign	0.17
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.0051	N
LIST_S2	Benign	0.13	T;T;T
MetaRNN	Benign	0.0016	T;T;T
MetaSVM	Benign	-0.77	T
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.33	T
PROVEAN	Benign	0.16	N;N;N
REVEL	Uncertain	0.35
Sift	Benign	0.70	T;T;T
Sift4G	Benign	0.26	T;T;T
Polyphen		0.0	.;B;.
Vest4		0.047
MPC		0.20
ClinPred		0.0013	T
GERP RS		-4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.034
gMVP		0.27

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs11549936; hg19: chr19-41916549; COSMIC: COSV54198869; COSMIC: COSV54198869;