6-80273153-C-T

Variant names:

• chr6-80273153-C-T
• rs398124603
• NM_183050.4:c.970C>T

Variant summary

Our verdict is Pathogenic. The variant received 22 ACMG points: 22P and 0B. PVS1 PS3 PM2 PP5_Very_Strong

The NM_183050.4(BCKDHB):​c.970C>T​(p.Arg324*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000026 in 1,613,042 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 Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000465668: Functional studies in patient lymphoblasts carrying the p.Arg324Ter variant demonstrate that variant BCKD enzyme activity is <1% of that of the control enzyme activity. Western blotting experiments showed that the variant resulted in a truncated protein which was not detected in the mitochondria suggesting that the missing amino acids may be necessary for tetramer formation (McConnell et al. 1997" and additional evidence is available in ClinVar. Synonymous variant affecting the same amino acid position (i.e. R324R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000027 (0 hom.)
• Consequence: BCKDHB NM_183050.4 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:14
• Conservation: PhyloP100: 1.67
• Publications: 9 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 22 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV000465668: Functional studies in patient lymphoblasts carrying the p.Arg324Ter variant demonstrate that variant BCKD enzyme activity is <1% of that of the control enzyme activity. Western blotting experiments showed that the variant resulted in a truncated protein which was not detected in the mitochondria suggesting that the missing amino acids may be necessary for tetramer formation (McConnell et al. 1997; Nellis et al. 2003).; SCV000916673: The most pronounced variant effect results in <10% of normal activity (McConnell_1997).
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 6-80273153-C-T is Pathogenic according to our data. Variant chr6-80273153-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 96621.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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.970C>T	p.Arg324*	stop_gained	Exon 9 of 10	NP_898871.1	P21953-1
	BCKDHB	NM_001424035.1		c.970C>T	p.Arg324*	stop_gained	Exon 9 of 10	NP_001410964.1
	BCKDHB	NM_000056.5		c.970C>T	p.Arg324*	stop_gained	Exon 9 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.970C>T	p.Arg324*	stop_gained	Exon 9 of 10	ENSP00000318351.5	P21953-1
	BCKDHB	ENST00000356489.9	TSL:1	c.970C>T	p.Arg324*	stop_gained	Exon 9 of 11	ENSP00000348880.5	P21953-1
	BCKDHB	ENST00000929318.1		c.970C>T	p.Arg324*	stop_gained	Exon 9 of 11	ENSP00000599377.1

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 152034 Hom.: 0 Cov.: 33

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: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000598 AC: 15 AN: 250890 AF XY: 0.0000590

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.000203

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000529

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000274 AC: 40 AN: 1461008 Hom.: 0 Cov.: 30 AF XY: 0.0000248 AC XY: 18 AN XY: 726822

African (AFR) AF: 0.0000598 AC: 2 AN: 33440

American (AMR) AF: 0.000134 AC: 6 AN: 44672

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26096

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39660

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53384

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.0000216 AC: 24 AN: 1111396

Other (OTH) AF: 0.0000663 AC: 4 AN: 60356

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 152034 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74262

African (AFR) AF: 0.00 AC: 0 AN: 41398

American (AMR) AF: 0.00 AC: 0 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10596

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 67998

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.0000224 Hom.: 0

Bravo AF: 0.0000416

ExAC AF: 0.0000741 AC: 9

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
5	-	-	Maple syrup urine disease (5)
3	-	-	Maple syrup urine disease type 1A (3)
3	-	-	Maple syrup urine disease type 1B (3)
3	-	-	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.62
CADD	Pathogenic	39
DANN	Uncertain	1.0
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.93	D
PhyloP100		1.7
Vest4		0.94
GERP RS		3.9
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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: rs398124603; hg19: chr6-80982870; COSMIC: COSV57516388;