rs1554194690

Positions:

• chr6-80200998-GAGTGATGTTACTCT-G

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_183050.4(BCKDHB):​c.811_824del​(p.Asp271CysfsTer25) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,762 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: BCKDHB NM_183050.4 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 9.44

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 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 6-80200998-GAGTGATGTTACTCT-G is Pathogenic according to our data. Variant chr6-80200998-GAGTGATGTTACTCT-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 557213.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.811_824del	p.Asp271CysfsTer25	frameshift_variant	7/10	ENST00000320393.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BCKDHB	ENST00000320393.9	c.811_824del	p.Asp271CysfsTer25	frameshift_variant	7/10	1	NM_183050.4	P1
BCKDHB	ENST00000356489.9	c.811_824del	p.Asp271CysfsTer25	frameshift_variant	7/11	1		P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460762 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 726746

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: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Maple syrup urine disease Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Mar 19, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Aug 30, 2022	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 557213). This variant is also known as c.808_821del, p.Ser270_Leu274del. This premature translational stop signal has been observed in individual(s) with maple syrup urine disease (PMID: 17922217). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Asp271Cysfs*25) in the BCKDHB gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BCKDHB are known to be pathogenic (PMID: 16786533, 22593002). -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1554194690; hg19: chr6-80910715;