rs74586298

Positions:

• chr19-41422992-G-A
• chr19-41422992-G-C

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.996-6G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0054 in 1,608,210 control chromosomes in the GnomAD database, including 382 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.028 (185 hom., cov: 33)
  • Exomes 𝑓: 0.0030 (197 hom.)
• Consequence: BCKDHA NM_000709.4 splice_region, intron
• Scores: Splicing: ADA: 0.00002503
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.808

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 19-41422992-G-A is Benign according to our data. Variant chr19-41422992-G-A is described in ClinVar as [Benign]. Clinvar id is 93390.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0938 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BCKDHA	NM_000709.4	c.996-6G>A		splice_region_variant, intron_variant		ENST00000269980.7	NP_000700.1
BCKDHA	NM_001164783.2	c.993-6G>A		splice_region_variant, intron_variant			NP_001158255.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BCKDHA	ENST00000269980.7	c.996-6G>A		splice_region_variant, intron_variant		1	NM_000709.4	ENSP00000269980.2
ENSG00000255730	ENST00000540732.3	c.1098-6G>A		splice_region_variant, intron_variant		2		ENSP00000443246.1
BCKDHA	ENST00000457836.6	c.999G>A	p.Leu333Leu	synonymous_variant	8/9	2		ENSP00000416000.2
BCKDHA	ENST00000542943.5	c.909-6G>A		splice_region_variant, intron_variant		5		ENSP00000440345.1

Frequencies

GnomAD3 genomes AF: 0.0278 AC: 4222 AN: 152022 Hom.: 183 Cov.: 33

Gnomad AFR AF: 0.0960

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0107

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000456

Gnomad OTH AF: 0.0220

GnomAD3 exomes AF: 0.00723 AC: 1722 AN: 238176 Hom.: 58 AF XY: 0.00548 AC XY: 707 AN XY: 128900

Gnomad AFR exome AF: 0.0969

Gnomad AMR exome AF: 0.00568

Gnomad ASJ exome AF: 0.00153

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000171

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000401

Gnomad OTH exome AF: 0.00344

GnomAD4 exome AF: 0.00305 AC: 4438 AN: 1456070 Hom.: 197 Cov.: 35 AF XY: 0.00261 AC XY: 1889 AN XY: 723742

Gnomad4 AFR exome AF: 0.0999

Gnomad4 AMR exome AF: 0.00587

Gnomad4 ASJ exome AF: 0.00173

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000282

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000279

Gnomad4 OTH exome AF: 0.00742

GnomAD4 genome AF: 0.0279 AC: 4246 AN: 152140 Hom.: 185 Cov.: 33 AF XY: 0.0264 AC XY: 1965 AN XY: 74362

Gnomad4 AFR AF: 0.0963

Gnomad4 AMR AF: 0.0107

Gnomad4 ASJ AF: 0.00259

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000456

Gnomad4 OTH AF: 0.0217

Alfa AF: 0.0104 Hom.: 35

Bravo AF: 0.0320

Asia WGS AF: 0.00520 AC: 18 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 08, 2016	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. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 23, 2013	- -

Maple syrup urine disease Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

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	-0.85
CADD	Benign	0.49
DANN	Benign	0.70

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000025
dbscSNV1_RF	Benign	0.0040
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: rs74586298; hg19: chr19-41928897;