19-41397840-AT-A

Position:

• chr19-41397840-AT-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_000709.4(BCKDHA):​c.14del​(p.Ile5ThrfsTer9) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,824 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. I5I) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: BCKDHA NM_000709.4 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: -0.345

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 Pathogenic. Variant got 14 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 7 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 19-41397840-AT-A is Pathogenic according to our data. Variant chr19-41397840-AT-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 93349.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.14del	p.Ile5ThrfsTer9	frameshift_variant	1/9	ENST00000269980.7	NP_000700.1
BCKDHA	NM_001164783.2	c.14del	p.Ile5ThrfsTer9	frameshift_variant	1/9		NP_001158255.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BCKDHA	ENST00000269980.7	c.14del	p.Ile5ThrfsTer9	frameshift_variant	1/9	1	NM_000709.4	ENSP00000269980	P1
BCKDHA	ENST00000457836.6	c.14del	p.Ile5ThrfsTer9	frameshift_variant	1/9	2		ENSP00000416000
BCKDHA	ENST00000542943.5	c.14del	p.Ile5ThrfsTer9	frameshift_variant	1/7	5		ENSP00000440345
BCKDHA	ENST00000538423.5	n.34del		non_coding_transcript_exon_variant	1/5	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461824 Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4 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: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000629

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Maple syrup urine disease Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	This sequence change creates a premature translational stop signal (p.Ile5Thrfs*9) in the BCKDHA gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BCKDHA are known to be pathogenic (PMID: 16786533, 22593002). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with BCKDHA-related conditions. ClinVar contains an entry for this variant (Variation ID: 93349). For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 12, 2023	Variant summary: BCKDHA c.14delT (p.Ile5ThrfsX9) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251098 control chromosomes (gnomAD). To our knowledge, no occurrence of c.14delT in individuals affected with Maple Syrup Urine Disease and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Apr 20, 2023	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Aug 23, 2013

- -

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: rs398123494; hg19: chr19-41903745;