rs1554189815

chr6-80168914-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The NM_183050.4(BCKDHB):c.517G>T(p.Asp173Tyr) variant causes a missense change. 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: BCKDHB NM_183050.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.73

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_183050.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.881

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BCKDHB	NM_183050.4	c.517G>T	p.Asp173Tyr	missense_variant	5/10	ENST00000320393.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BCKDHB	ENST00000320393.9	c.517G>T	p.Asp173Tyr	missense_variant	5/10	1	NM_183050.4	P1
BCKDHB	ENST00000356489.9	c.517G>T	p.Asp173Tyr	missense_variant	5/11	1		P1
BCKDHB	ENST00000369760.8	c.517G>T	p.Asp173Tyr	missense_variant	5/6	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Maple syrup urine disease Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Counsyl

Oct 07, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
Cadd	Pathogenic	32
Dann	Uncertain	0.99
Eigen	Pathogenic	0.70
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.99	D;.;D
M_CAP	Uncertain	0.25	D
MetaRNN	Pathogenic	0.88	D;D;D
MetaSVM	Pathogenic	0.80	D
MutationAssessor	Benign	0.81	L;L;L
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-3.4	D;D;D
REVEL	Pathogenic	0.81
Sift	Uncertain	0.0030	D;D;D
Sift4G	Uncertain	0.0040	D;D;D
Polyphen		0.99	.;D;D
Vest4		0.80
MutPred		0.69		Loss of helix (P = 0.0167);Loss of helix (P = 0.0167);Loss of helix (P = 0.0167);
MVP		0.99
MPC		0.78
ClinPred		0.97	D
GERP RS		5.1
Varity_R		0.86
gMVP		0.93

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: rs1554189815; hg19: chr6-80878631;