rs190867671

chr6-80343774-T-Achr6-80343774-T-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_Moderate PM2 PP5_Very_Strong

The NM_183050.4(BCKDHB):c.1149T>A(p.Tyr383Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. Y383Y) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BCKDHB NM_183050.4 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 0.935

Genes affected

BCKDHB (HGNC:987): (branched chain keto acid dehydrogenase E1 subunit beta) This gene encodes the E1 beta subunit of branched-chain keto acid dehydrogenase, which is a multienzyme complex associated with the inner membrane of mitochondria. This enzyme complex functions in the catabolism of branched-chain amino acids. Mutations in this gene have been associated with maple syrup urine disease (MSUD), type 1B, a disease characterized by a maple syrup odor to the urine in addition to mental and physical retardation and feeding problems. Alternative splicing at this locus results in multiple transcript variants. [provided by RefSeq, Jan 2016]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0254 CDS is truncated, and there are 2 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 6-80343774-T-A is Pathogenic according to our data. Variant chr6-80343774-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 553268.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BCKDHB	NM_183050.4	c.1149T>A	p.Tyr383Ter	stop_gained	10/10	ENST00000320393.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BCKDHB	ENST00000320393.9	c.1149T>A	p.Tyr383Ter	stop_gained	10/10	1	NM_183050.4	P1
BCKDHB	ENST00000356489.9	c.1149T>A	p.Tyr383Ter	stop_gained	10/11	1		P1
BCKDHB	ENST00000491328.1	n.204T>A		non_coding_transcript_exon_variant	1/2	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

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:4

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 27, 2020	Variant summary: BCKDHB c.1149T>A (p.Tyr383X) 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. The variant was absent in 251330 control chromosomes. c.1149T>A has been reported in the literature as a homozygous variant in at-least one individual of Turkish ethnicity affected with classic Maple syrup urine disease (Nellis_2001) and has been subsequently cited by others (example, Henneke_2003). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity in patient fibroblasts (Henneke_2003). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as likely pathogenic citing overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Aug 10, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Nov 17, 2020	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the C-terminus of the BCKDHB protein. Other variant(s) that disrupt this region (p.Arg387*) have been determined to be pathogenic (PMID: 30228974, Invitae). This suggests that variants that disrupt this region of the protein are likely to be causative of disease. This variant has been observed in individual(s) with maple syrup urine disease (PMID: 11112664, 14517957). ClinVar contains an entry for this variant (Variation ID: 553268). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Tyr383*) in the BCKDHB gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 10 amino acid(s) of the BCKDHB protein. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
Cadd	Pathogenic	36
Dann	Uncertain	0.99
Eigen	Benign	0.15
Eigen_PC	Benign	-0.023
FATHMM_MKL	Uncertain	0.87	D
MutationTaster	Benign	1.0	D;D;D
Vest4		0.73
GERP RS		-0.48

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.23		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.23		Position offset: 38

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

Publications

LitVar

Other links and lift over

dbSNP: rs190867671; hg19: chr6-81053491;