rs284653

Positions:

• chr19-41422796-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.995+26C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.414 in 1,611,234 control chromosomes in the GnomAD database, including 144,759 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.37 (11350 hom., cov: 33)
  • Exomes 𝑓: 0.42 (133409 hom.)
• Consequence: BCKDHA NM_000709.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.248

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 (BayesDel_noAF=-0.86).
• BP6: Variant 19-41422796-C-T is Benign according to our data. Variant chr19-41422796-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 93386.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.44 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BCKDHA	NM_000709.4	c.995+26C>T		intron_variant		ENST00000269980.7
BCKDHA	NM_001164783.2	c.992+26C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BCKDHA	ENST00000269980.7	c.995+26C>T		intron_variant		1	NM_000709.4	P1
BCKDHA	ENST00000457836.6	c.929+26C>T		intron_variant		2
BCKDHA	ENST00000542943.5	c.908+26C>T		intron_variant		5
BCKDHA	ENST00000535632.5			downstream_gene_variant		3

Frequencies

GnomAD3 genomes AF: 0.370 AC: 56258 AN: 151864 Hom.: 11354 Cov.: 33

Gnomad AFR AF: 0.255

Gnomad AMI AF: 0.541

Gnomad AMR AF: 0.359

Gnomad ASJ AF: 0.402

Gnomad EAS AF: 0.0832

Gnomad SAS AF: 0.256

Gnomad FIN AF: 0.527

Gnomad MID AF: 0.418

Gnomad NFE AF: 0.445

Gnomad OTH AF: 0.376

GnomAD3 exomes AF: 0.374 AC: 92865 AN: 248348 Hom.: 19057 AF XY: 0.375 AC XY: 50491 AN XY: 134532

Gnomad AFR exome AF: 0.252

Gnomad AMR exome AF: 0.341

Gnomad ASJ exome AF: 0.410

Gnomad EAS exome AF: 0.0804

Gnomad SAS exome AF: 0.275

Gnomad FIN exome AF: 0.519

Gnomad NFE exome AF: 0.445

Gnomad OTH exome AF: 0.408

GnomAD4 exome AF: 0.419 AC: 611443 AN: 1459252 Hom.: 133409 Cov.: 67 AF XY: 0.416 AC XY: 301827 AN XY: 725952

Gnomad4 AFR exome AF: 0.248

Gnomad4 AMR exome AF: 0.340

Gnomad4 ASJ exome AF: 0.415

Gnomad4 EAS exome AF: 0.0706

Gnomad4 SAS exome AF: 0.278

Gnomad4 FIN exome AF: 0.516

Gnomad4 NFE exome AF: 0.448

Gnomad4 OTH exome AF: 0.394

GnomAD4 genome AF: 0.370 AC: 56257 AN: 151982 Hom.: 11350 Cov.: 33 AF XY: 0.369 AC XY: 27416 AN XY: 74278

Gnomad4 AFR AF: 0.254

Gnomad4 AMR AF: 0.359

Gnomad4 ASJ AF: 0.402

Gnomad4 EAS AF: 0.0836

Gnomad4 SAS AF: 0.256

Gnomad4 FIN AF: 0.527

Gnomad4 NFE AF: 0.445

Gnomad4 OTH AF: 0.374

Alfa AF: 0.429 Hom.: 13887

Bravo AF: 0.357

Asia WGS AF: 0.186 AC: 651 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 23, 2013	- -

Maple syrup urine disease Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jun 10, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 14, 2018

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.74
DANN	Benign	0.80

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: rs284653; hg19: chr19-41928701; COSMIC: COSV54197447; COSMIC: COSV54197447;