rs149899007

Variant names:

• chr19-41414162-G-A
• rs149899007
• NM_000709.4:c.484+5G>A

Your query was ambiguous. Multiple possible variants found:

• chr19-41414162-G-A
• chr19-41414162-G-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_000709.4(BCKDHA):​c.484+5G>A variant causes a splice region, intron change. The variant allele was found at a frequency of 0.00161 in 1,613,028 control chromosomes in the GnomAD database, including 70 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0030 (11 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (59 hom.)
• Consequence: BCKDHA NM_000709.4 splice_region, intron
• Scores: Splicing: ADA: 0.9986
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 3.77

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 19-41414162-G-A is Benign according to our data. Variant chr19-41414162-G-A is described in ClinVar as [Benign]. Clinvar id is 93362.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00302 (460/152348) while in subpopulation AMR AF= 0.0265 (405/15300). AF 95% confidence interval is 0.0243. There are 11 homozygotes in gnomad4. There are 248 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 11 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BCKDHA	NM_000709.4	c.484+5G>A		splice_region_variant, intron_variant	Intron 4 of 8	ENST00000269980.7	NP_000700.1
BCKDHA	NM_001164783.2	c.484+5G>A		splice_region_variant, intron_variant	Intron 4 of 8		NP_001158255.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BCKDHA	ENST00000269980.7	c.484+5G>A		splice_region_variant, intron_variant	Intron 4 of 8	1	NM_000709.4	ENSP00000269980.2
ENSG00000255730	ENST00000540732.3	c.586+5G>A		splice_region_variant, intron_variant	Intron 5 of 9	2		ENSP00000443246.1

Frequencies

GnomAD3 genomes AF: 0.00299 AC: 455 AN: 152230 Hom.: 11 Cov.: 32

Gnomad AFR AF: 0.00116

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00641 AC: 1600 AN: 249614 Hom.: 45 AF XY: 0.00469 AC XY: 635 AN XY: 135378

Gnomad AFR exome AF: 0.00125

Gnomad AMR exome AF: 0.0450

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000178

Gnomad OTH exome AF: 0.00344

GnomAD4 exome AF: 0.00146 AC: 2132 AN: 1460680 Hom.: 59 Cov.: 34 AF XY: 0.00122 AC XY: 884 AN XY: 726702

Gnomad4 AFR exome AF: 0.00117

Gnomad4 AMR exome AF: 0.0447

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000117

Gnomad4 OTH exome AF: 0.00133

GnomAD4 genome AF: 0.00302 AC: 460 AN: 152348 Hom.: 11 Cov.: 32 AF XY: 0.00333 AC XY: 248 AN XY: 74510

Gnomad4 AFR AF: 0.00115

Gnomad4 AMR AF: 0.0265

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000436 Hom.: 2

Bravo AF: 0.00529

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Feb 08, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Oct 20, 2015

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Maple syrup urine disease Benign:2

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not provided Benign:1

Jun 16, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

BCKDHA-related disorder Benign:1

Oct 13, 2021

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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). -

Maple syrup urine disease type 1A Benign:1

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.32
CADD	Benign	20
DANN	Benign	0.96

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Benign	0.69
SpliceAI score (max)		0.22		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.22		Position offset: -5

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs149899007; hg19: chr19-41920067;