rs398101222

Positions:

• chr19-41422962-G-GC

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_000709.4(BCKDHA):​c.996-33dupC variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.61 in 1,596,250 control chromosomes in the GnomAD database, including 301,111 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.66 (33815 hom., cov: 0)
  • Exomes 𝑓: 0.61 (267296 hom.)
• Consequence: BCKDHA NM_000709.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.230

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]

ENSG00000255730 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP6: Variant 19-41422962-G-GC is Benign according to our data. Variant chr19-41422962-G-GC is described in ClinVar as [Benign]. Clinvar id is 93389.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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	Protein	UniProt
BCKDHA	NM_000709.4	c.996-33dupC		intron_variant		ENST00000269980.7	NP_000700.1
BCKDHA	NM_001164783.2	c.993-33dupC		intron_variant			NP_001158255.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BCKDHA	ENST00000269980.7	c.996-33dupC		intron_variant		1	NM_000709.4	ENSP00000269980.2
ENSG00000255730	ENST00000540732.3	c.1098-33dupC		intron_variant		2		ENSP00000443246.1
BCKDHA	ENST00000457836.6	c.972dupC	p.Thr325fs	frameshift_variant	8/9	2		ENSP00000416000.2
BCKDHA	ENST00000542943.5	c.909-33dupC		intron_variant		5		ENSP00000440345.1

Frequencies

GnomAD3 genomes AF: 0.656 AC: 99667 AN: 151840 Hom.: 33773 Cov.: 0

Gnomad AFR AF: 0.820

Gnomad AMI AF: 0.770

Gnomad AMR AF: 0.560

Gnomad ASJ AF: 0.627

Gnomad EAS AF: 0.432

Gnomad SAS AF: 0.588

Gnomad FIN AF: 0.660

Gnomad MID AF: 0.636

Gnomad NFE AF: 0.600

Gnomad OTH AF: 0.638

GnomAD3 exomes AF: 0.590 AC: 129959 AN: 220434 Hom.: 39155 AF XY: 0.589 AC XY: 70189 AN XY: 119194

Gnomad AFR exome AF: 0.823

Gnomad AMR exome AF: 0.479

Gnomad ASJ exome AF: 0.624

Gnomad EAS exome AF: 0.425

Gnomad SAS exome AF: 0.586

Gnomad FIN exome AF: 0.657

Gnomad NFE exome AF: 0.604

Gnomad OTH exome AF: 0.607

GnomAD4 exome AF: 0.606 AC: 874637 AN: 1444292 Hom.: 267296 Cov.: 36 AF XY: 0.604 AC XY: 433268 AN XY: 716882

Gnomad4 AFR exome AF: 0.832

Gnomad4 AMR exome AF: 0.483

Gnomad4 ASJ exome AF: 0.623

Gnomad4 EAS exome AF: 0.458

Gnomad4 SAS exome AF: 0.581

Gnomad4 FIN exome AF: 0.654

Gnomad4 NFE exome AF: 0.607

Gnomad4 OTH exome AF: 0.613

GnomAD4 genome AF: 0.657 AC: 99762 AN: 151958 Hom.: 33815 Cov.: 0 AF XY: 0.654 AC XY: 48545 AN XY: 74270

Gnomad4 AFR AF: 0.821

Gnomad4 AMR AF: 0.560

Gnomad4 ASJ AF: 0.627

Gnomad4 EAS AF: 0.433

Gnomad4 SAS AF: 0.587

Gnomad4 FIN AF: 0.660

Gnomad4 NFE AF: 0.600

Gnomad4 OTH AF: 0.638

Alfa AF: 0.624 Hom.: 5474

Bravo AF: 0.656

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

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

Jul 14, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

BCKDHA-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 22, 2024

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

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: rs3217385; hg19: chr19-41928867;