6-80106703-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_183050.4(BCKDHB):c.10G>A(p.Val4Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000387 in 1,551,588 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V4L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000029 (0 hom.)
• Consequence: BCKDHB NM_183050.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: -0.159

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_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.04751596).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BCKDHB	NM_183050.4	c.10G>A	p.Val4Ile	missense_variant	1/10	ENST00000320393.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BCKDHB	ENST00000320393.9	c.10G>A	p.Val4Ile	missense_variant	1/10	1	NM_183050.4	P1
BCKDHB	ENST00000356489.9	c.10G>A	p.Val4Ile	missense_variant	1/11	1		P1
BCKDHB	ENST00000369760.8	c.10G>A	p.Val4Ile	missense_variant	1/6	3

Frequencies

GnomAD3 genomes AF: 0.000131 AC: 20 AN: 152234 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000410

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000466 AC: 7 AN: 150212 Hom.: 0 AF XY: 0.0000124 AC XY: 1 AN XY: 80772

Gnomad AFR exome AF: 0.000539

Gnomad AMR exome AF: 0.0000796

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000183

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000286 AC: 40 AN: 1399354 Hom.: 0 Cov.: 32 AF XY: 0.0000275 AC XY: 19 AN XY: 690644

Gnomad4 AFR exome AF: 0.00101

Gnomad4 AMR exome AF: 0.0000831

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000370

Gnomad4 OTH exome AF: 0.0000173

GnomAD4 genome AF: 0.000131 AC: 20 AN: 152234 Hom.: 0 Cov.: 32 AF XY: 0.000148 AC XY: 11 AN XY: 74366

Gnomad4 AFR AF: 0.000410

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000566 Hom.: 0

Bravo AF: 0.000174

ExAC AF: 0.0000289 AC: 3

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

Maple syrup urine disease Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Oct 31, 2022

This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 4 of the BCKDHB protein (p.Val4Ile). This variant is present in population databases (rs774255890, gnomAD 0.06%). This variant has not been reported in the literature in individuals affected with BCKDHB-related conditions. ClinVar contains an entry for this variant (Variation ID: 966957). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Maple syrup urine disease type 1B Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

Jul 23, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.20
Cadd	Benign	5.5
Dann	Benign	0.90
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.014	N
LIST_S2	Benign	0.54	T;.;T
M_CAP	Pathogenic	0.62	D
MetaRNN	Benign	0.048	T;T;T
MetaSVM	Uncertain	-0.24	T
MutationAssessor	Benign	1.7	L;L;L
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-0.080	N;N;N
REVEL	Benign	0.11
Sift	Benign	0.36	T;T;T
Sift4G	Benign	0.33	T;T;T
Polyphen		0.0	.;B;B
Vest4		0.23
MutPred		0.32		Loss of disorder (P = 0.1776);Loss of disorder (P = 0.1776);Loss of disorder (P = 0.1776);
MVP		0.58
MPC		0.16
ClinPred		0.046	T
GERP RS		-4.0
Varity_R		0.027
gMVP		0.32

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: rs774255890; hg19: chr6-80816420;