GeneBe

rs1167005638

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1PM2

The NM_183050.4(BCKDHB):​c.714delT​(p.Phe238LeufsTer16) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,454,698 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. F238F) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

BCKDHB
NM_183050.4 frameshift

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.25

Publications

0 publications found
Variant links:
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: ClinGen, G2P, Myriad Women’s Health
  • 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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 10 ACMG points.

PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
BCKDHBNM_183050.4 linkc.714delT p.Phe238LeufsTer16 frameshift_variant Exon 6 of 10 ENST00000320393.9 NP_898871.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
BCKDHBENST00000320393.9 linkc.714delT p.Phe238LeufsTer16 frameshift_variant Exon 6 of 10 1 NM_183050.4 ENSP00000318351.5
BCKDHBENST00000356489.9 linkc.714delT p.Phe238LeufsTer16 frameshift_variant Exon 6 of 11 1 ENSP00000348880.5

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.87e-7
AC:
1
AN:
1454698
Hom.:
0
Cov.:
29
AF XY:
0.00
AC XY:
0
AN XY:
723410
show subpopulations
⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
African (AFR)
AF:
0.00
AC:
0
AN:
33284
American (AMR)
AF:
0.00
AC:
0
AN:
44406
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
25998
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39420
South Asian (SAS)
AF:
0.00
AC:
0
AN:
84880
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53210
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
4386
European-Non Finnish (NFE)
AF:
9.02e-7
AC:
1
AN:
1109166
Other (OTH)
AF:
0.00
AC:
0
AN:
59948
⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.225
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome
Cov.:
32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
PhyloP100
7.2

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

Other links and lift over

dbSNP: rs1167005638; hg19: chr6-80881073; API