rs200609312

chr6-80127535-TG-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 2P and 12B. PM2 BP6_Very_Strong BS1

The NM_183050.4(BCKDHB):c.197-11del variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00753 in 1,395,710 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0084 (0 hom.)
• Consequence: BCKDHB NM_183050.4 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.218

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 Benign. Variant got -10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 6-80127535-TG-T is Benign according to our data. Variant chr6-80127535-TG-T is described in ClinVar as [Benign]. Clinvar id is 263076.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-80127535-TG-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population eas. gnomad4_exome allele frequency = 0.00844 (10498/1244034) while in subpopulation EAS AF= 0.0219 (611/27920). AF 95% confidence interval is 0.0204. There are 0 homozygotes in gnomad4_exome. There are 5147 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BCKDHB	NM_183050.4	c.197-11del		splice_polypyrimidine_tract_variant, intron_variant		ENST00000320393.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BCKDHB	ENST00000320393.9	c.197-11del		splice_polypyrimidine_tract_variant, intron_variant		1	NM_183050.4	P1
BCKDHB	ENST00000356489.9	c.197-11del		splice_polypyrimidine_tract_variant, intron_variant		1		P1
BCKDHB	ENST00000369760.8	c.197-11del		splice_polypyrimidine_tract_variant, intron_variant		3
BCKDHB	ENST00000486968.1	n.111-11del		splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.0000462 AC: 7 AN: 151572 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000191

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000590

Gnomad OTH AF: 0.000480

GnomAD4 exome AF: 0.00844 AC: 10498 AN: 1244034 Hom.: 0 Cov.: 31 AF XY: 0.00836 AC XY: 5147 AN XY: 615650

Gnomad4 AFR exome AF: 0.00194

Gnomad4 AMR exome AF: 0.0111

Gnomad4 ASJ exome AF: 0.00661

Gnomad4 EAS exome AF: 0.0219

Gnomad4 SAS exome AF: 0.0142

Gnomad4 FIN exome AF: 0.00699

Gnomad4 NFE exome AF: 0.00786

Gnomad4 OTH exome AF: 0.00943

GnomAD4 genome AF: 0.0000462 AC: 7 AN: 151676 Hom.: 0 Cov.: 32 AF XY: 0.0000270 AC XY: 2 AN XY: 74142

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000191

Gnomad4 NFE AF: 0.0000590

Gnomad4 OTH AF: 0.000476

Alfa AF: 0.0260 Hom.: 0

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Maple syrup urine disease Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

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: rs200609312; hg19: chr6-80837252; COSMIC: COSV57510518;