rs199725420

Positions:

• chr19-41414045-C-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_000709.4(BCKDHA):​c.376-4C>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00208 in 1,613,302 control chromosomes in the GnomAD database, including 44 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 0.0015 (6 hom., cov: 32)
  • Exomes 𝑓: 0.0021 (38 hom.)
• Consequence: BCKDHA NM_000709.4 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0001741
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.57

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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.41).
• BP6: Variant 19-41414045-C-T is Benign according to our data. Variant chr19-41414045-C-T is described in ClinVar as [Benign]. Clinvar id is 93359.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-41414045-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00155 (236/152310) while in subpopulation SAS AF= 0.0222 (107/4826). AF 95% confidence interval is 0.0188. There are 6 homozygotes in gnomad4. There are 147 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BCKDHA	NM_000709.4	c.376-4C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000269980.7
BCKDHA	NM_001164783.2	c.376-4C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BCKDHA	ENST00000269980.7	c.376-4C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_000709.4	P1

Frequencies

GnomAD3 genomes AF: 0.00154 AC: 234 AN: 152192 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00151

Gnomad ASJ AF: 0.00691

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0217

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000970

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00359 AC: 899 AN: 250502 Hom.: 10 AF XY: 0.00467 AC XY: 633 AN XY: 135678

Gnomad AFR exome AF: 0.000124

Gnomad AMR exome AF: 0.00159

Gnomad ASJ exome AF: 0.00736

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0208

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.000850

Gnomad OTH exome AF: 0.00523

GnomAD4 exome AF: 0.00214 AC: 3122 AN: 1460992 Hom.: 38 Cov.: 34 AF XY: 0.00275 AC XY: 1998 AN XY: 726808

Gnomad4 AFR exome AF: 0.000120

Gnomad4 AMR exome AF: 0.00159

Gnomad4 ASJ exome AF: 0.00662

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0217

Gnomad4 FIN exome AF: 0.000208

Gnomad4 NFE exome AF: 0.000722

Gnomad4 OTH exome AF: 0.00245

GnomAD4 genome AF: 0.00155 AC: 236 AN: 152310 Hom.: 6 Cov.: 32 AF XY: 0.00197 AC XY: 147 AN XY: 74468

Gnomad4 AFR AF: 0.000241

Gnomad4 AMR AF: 0.00150

Gnomad4 ASJ AF: 0.00691

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0222

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.000970

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00157 Hom.: 1

Bravo AF: 0.000990

Asia WGS AF: 0.00664 AC: 23 AN: 3478

EpiCase AF: 0.00125

EpiControl AF: 0.00107

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	Apr 25, 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)	Jan 31, 2017	- -

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	Invitae	Jan 31, 2024	- -

BCKDHA-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 22, 2019

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

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	-0.41
CADD	Benign	8.9
DANN	Benign	0.87

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00017
dbscSNV1_RF	Benign	0.018
SpliceAI score (max)		0.010		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: rs199725420; hg19: chr19-41919950;