6-80106695-T-C

Position:

• chr6-80106695-T-C

Variant summary

Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PVS1 PS1_Moderate PM2 PP5_Very_Strong

The NM_183050.4(BCKDHB):​c.2T>C​(p.Met1?) variant causes a start lost 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 (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: BCKDHB NM_183050.4 start_lost
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 3.08

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 20 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 6-80106695-T-C is Pathogenic according to our data. Variant chr6-80106695-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 553562.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.2T>C	p.Met1?	start_lost	1/10	ENST00000320393.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BCKDHB	ENST00000320393.9	c.2T>C	p.Met1?	start_lost	1/10	1	NM_183050.4	P1
BCKDHB	ENST00000356489.9	c.2T>C	p.Met1?	start_lost	1/11	1		P1
BCKDHB	ENST00000369760.8	c.2T>C	p.Met1?	start_lost	1/6	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

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

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 09, 2022	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 553562). Disruption of the initiator codon has been observed in individual(s) with maple syrup urine disease (PMID: 26257134, 31980395, 32515140, 33300147; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change affects the initiator methionine of the BCKDHB mRNA. The next in-frame methionine is located at codon 71. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Aug 29, 2017	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.41
CADD	Benign	22
DANN	Benign	0.91
DEOGEN2	Benign	0.28	.;T;T
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.098
FATHMM_MKL	Benign	0.54	D
LIST_S2	Uncertain	0.90	D;.;D
M_CAP	Pathogenic	1.0	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Uncertain	0.30	D
MutationTaster	Benign	1.0	D;D;D;D
PROVEAN	Benign	-0.67	N;N;N
REVEL	Pathogenic	0.65
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		0.12	.;B;B
Vest4		0.83
MutPred		0.84		Loss of stability (P = 0.0404);Loss of stability (P = 0.0404);Loss of stability (P = 0.0404);
MVP		0.98
ClinPred		1.0	D
GERP RS		4.2
Varity_R		0.92
gMVP		0.68

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: rs940391887; hg19: chr6-80816412;