6-80106696-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PVS1_SupportingPM2PP5_Moderate

The NM_183050.4(BCKDHB):​c.3G>A​(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.000000712 in 1,403,514 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 Pathogenic (★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

BCKDHB
NM_183050.4 start_lost

Scores

6
4
6

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 4.46
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PVS1
Start lost variant, no pathogenic variants between lost start and next in-frame start position. Next in-frame start position is after 210 CDS bases. Genomic position: 80127560. Lost 0.178 part of the original CDS.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 6-80106696-G-A is Pathogenic according to our data. Variant chr6-80106696-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 224057.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
BCKDHBNM_183050.4 linkc.3G>A p.Met1? start_lost Exon 1 of 10 ENST00000320393.9 NP_898871.1 P21953-1A0A140VKB3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
BCKDHBENST00000320393.9 linkc.3G>A p.Met1? start_lost Exon 1 of 10 1 NM_183050.4 ENSP00000318351.5 P21953-1
BCKDHBENST00000356489.9 linkc.3G>A p.Met1? start_lost Exon 1 of 11 1 ENSP00000348880.5 P21953-1
BCKDHBENST00000369760.8 linkc.3G>A p.Met1? start_lost Exon 1 of 6 3 ENSP00000358775.4 P21953-2

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
7.12e-7
AC:
1
AN:
1403514
Hom.:
0
Cov.:
32
AF XY:
0.00000144
AC XY:
1
AN XY:
692916
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000125
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Maple syrup urine disease Pathogenic:1
Jan 01, 2014
Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.63
D
BayesDel_noAF
Pathogenic
0.26
CADD
Benign
23
DANN
Uncertain
0.98
DEOGEN2
Benign
0.28
.;T;T
Eigen
Benign
0.0083
Eigen_PC
Benign
0.13
FATHMM_MKL
Benign
0.64
D
LIST_S2
Uncertain
0.90
D;.;D
M_CAP
Pathogenic
1.0
D
MetaRNN
Pathogenic
0.99
D;D;D
MetaSVM
Uncertain
0.46
D
PROVEAN
Benign
-0.48
N;N;N
REVEL
Uncertain
0.58
Sift
Pathogenic
0.0
D;D;D
Sift4G
Pathogenic
0.0
D;D;D
Polyphen
0.12
.;B;B
Vest4
0.91
MutPred
0.87
Loss of solvent accessibility (P = 0.0155);Loss of solvent accessibility (P = 0.0155);Loss of solvent accessibility (P = 0.0155);
MVP
0.98
ClinPred
1.0
D
GERP RS
5.3
Varity_R
0.96
gMVP
0.61

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs869312128; hg19: chr6-80816413; API