rs755691417

Positions:

• chr19-41424549-CTGG-C

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PM4_Supporting PP5_Very_Strong

The NM_000709.4(BCKDHA):​c.1280_1282delTGG​(p.Leu427_Ala428delinsPro) variant causes a disruptive inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,798 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: BCKDHA NM_000709.4 disruptive_inframe_deletion
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3 U:1
• Conservation: PhyloP100: 7.40

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 Pathogenic. Variant got 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_000709.4. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 19-41424549-CTGG-C is Pathogenic according to our data. Variant chr19-41424549-CTGG-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 557742.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BCKDHA	NM_000709.4	c.1280_1282delTGG	p.Leu427_Ala428delinsPro	disruptive_inframe_deletion	9/9	ENST00000269980.7	NP_000700.1
BCKDHA	NM_001164783.2	c.1277_1279delTGG	p.Leu426_Ala427delinsPro	disruptive_inframe_deletion	9/9		NP_001158255.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BCKDHA	ENST00000269980.7	c.1280_1282delTGG	p.Leu427_Ala428delinsPro	disruptive_inframe_deletion	9/9	1	NM_000709.4	ENSP00000269980.2
ENSG00000255730	ENST00000540732.3	c.1382_1384delTGG	p.Leu461_Ala462delinsPro	disruptive_inframe_deletion	10/10	2		ENSP00000443246.1
BCKDHA	ENST00000544905.1	c.109_111delTGG	p.Trp37del	conservative_inframe_deletion	2/2	2		ENSP00000445727.1
BCKDHA	ENST00000457836.6	c.1289_1291delTGG	p.Leu430_Ala431delinsPro	disruptive_inframe_deletion	9/9	2		ENSP00000416000.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000400 AC: 1 AN: 250104 Hom.: 0 AF XY: 0.00000739 AC XY: 1 AN XY: 135300

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461798 Hom.: 0 AF XY: 0.00000275 AC XY: 2 AN XY: 727200

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Maple syrup urine disease Pathogenic:2 Uncertain:1

Uncertain significance, flagged submission	clinical testing	Counsyl	Apr 11, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 20, 2022	This variant, c.1280_1282del, is a complex sequence change that results in the deletion of 2 and insertion of 1 amino acid(s) in the BCKDHA protein (p.Leu427_Ala428delinsPro). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 557742). This variant has been observed in individual(s) with maple syrup urine disease (PMID: 21844576, 31980395; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs755691417, gnomAD 0.006%). -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -

Maple syrup urine disease type 1A Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Dec 10, 2023

- -

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: rs755691417; hg19: chr19-41930454;