rs869312128

chr6-80106696-G-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1 PS1_Moderate PM2 PP5_Moderate

The NM_183050.4(BCKDHB):c.3G>A(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.000000712 in 1,403,514 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: BCKDHB NM_183050.4 start_lost
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 4.46

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 14 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PS1: Another start lost variant in NM_183050.4 (BCKDHB) was described as [Likely_pathogenic] in ClinVar as 551456
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 6-80106696-G-A is Pathogenic according to our data. Variant chr6-80106696-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 224057.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BCKDHB	NM_183050.4	c.3G>A	p.Met1?	start_lost	1/10	ENST00000320393.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BCKDHB	ENST00000320393.9	c.3G>A	p.Met1?	start_lost	1/10	1	NM_183050.4	P1
BCKDHB	ENST00000356489.9	c.3G>A	p.Met1?	start_lost	1/11	1		P1
BCKDHB	ENST00000369760.8	c.3G>A	p.Met1?	start_lost	1/6	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.12e-7 AC: 1 AN: 1403514 Hom.: 0 Cov.: 32 AF XY: 0.00000144 AC XY: 1 AN XY: 692916

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: 0.0000125

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Maple syrup urine disease Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital

Jan 01, 2014

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.26
Cadd	Benign	23
Dann	Uncertain	0.98
Eigen	Benign	0.0083
Eigen_PC	Benign	0.13
FATHMM_MKL	Benign	0.64	D
LIST_S2	Uncertain	0.90	D;.;D
M_CAP	Pathogenic	1.0	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Uncertain	0.46	D
MutationTaster	Benign	1.0	D;D;D;D
PROVEAN	Benign	-0.48	N;N;N
REVEL	Uncertain	0.58
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		0.12	.;B;B
Vest4		0.91
MutPred		0.87		Loss of solvent accessibility (P = 0.0155);Loss of solvent accessibility (P = 0.0155);Loss of solvent accessibility (P = 0.0155);
MVP		0.98
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.96
gMVP		0.61

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: rs869312128; hg19: chr6-80816413;