rs869312130

Variant names:

• chr6-80167735-T-A
• rs869312130
• NM_183050.4:c.401T>A

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM1 PM2 PP2 PP3_Strong PP5_Moderate

The NM_183050.4(BCKDHB):​c.401T>A​(p.Ile134Asn) 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 Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. I134I) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: BCKDHB NM_183050.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 5.92
• Publications: 1 publications found

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]

BCKDHB Gene-Disease associations (from GenCC):

• maple syrup urine disease type 1B

  Inheritance: AR Classification: DEFINITIVE Submitted by: G2P, Myriad Women’s Health, ClinGen
• maple syrup urine disease

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• classic maple syrup urine disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• intermediate maple syrup urine disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• intermittent maple syrup urine disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• thiamine-responsive maple syrup urine disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 11 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, 2 uncertain in NM_183050.4
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 51 curated pathogenic missense variants (we use a threshold of 10). The gene has 5 curated benign missense variants. Gene score misZ: -0.17637 (below the threshold of 3.09). Trascript score misZ: -0.0026186 (below the threshold of 3.09). GenCC associations: The gene is linked to classic maple syrup urine disease, thiamine-responsive maple syrup urine disease, intermittent maple syrup urine disease, intermediate maple syrup urine disease, maple syrup urine disease type 1B, maple syrup urine disease.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.942
• PP5: Variant 6-80167735-T-A is Pathogenic according to our data. Variant chr6-80167735-T-A is described in ClinVar as Pathogenic. ClinVar VariationId is 224060.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_183050.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BCKDHB	NM_183050.4	MANE Select	c.401T>A	p.Ile134Asn	missense	Exon 4 of 10	NP_898871.1	P21953-1
	BCKDHB	NM_001424035.1		c.401T>A	p.Ile134Asn	missense	Exon 4 of 10	NP_001410964.1
	BCKDHB	NM_000056.5		c.401T>A	p.Ile134Asn	missense	Exon 4 of 11	NP_000047.1	A0A140VKB3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BCKDHB	ENST00000320393.9	TSL:1 MANE Select	c.401T>A	p.Ile134Asn	missense	Exon 4 of 10	ENSP00000318351.5	P21953-1
	BCKDHB	ENST00000356489.9	TSL:1	c.401T>A	p.Ile134Asn	missense	Exon 4 of 11	ENSP00000348880.5	P21953-1
	BCKDHB	ENST00000929318.1		c.401T>A	p.Ile134Asn	missense	Exon 4 of 11	ENSP00000599377.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Maple syrup urine disease (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.14
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.73	D
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.57	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Uncertain	0.74	D
MutationAssessor	Benign	1.9	L
PhyloP100		5.9
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-6.7	D
REVEL	Pathogenic	0.81
Sift	Benign	0.086	T
Sift4G	Uncertain	0.048	D
Polyphen		1.0	D
Vest4		0.98
MutPred		0.58		Loss of helix (P = 0.079)
MVP		0.99
MPC		1.0
ClinPred		0.97	D
GERP RS		3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.87
gMVP		0.99
Mutation Taster		=1/99	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs869312130; hg19: chr6-80877452;