rs767154711

chr1-100206294-C-Achr1-100206294-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PP3_Strong

The NM_001918.5(DBT):c.1217G>T(p.Gly406Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000187 in 1,608,126 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 Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.0000067 ( 0 hom., cov: 30)

Exomes 𝑓: 0.000020 ( 0 hom. )

Consequence

DBT
NM_001918.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 7.48

Variant links:

Genes affected

DBT (HGNC:2698): (dihydrolipoamide branched chain transacylase E2) The branched-chain alpha-keto acid dehydrogenase complex (BCKD) is an inner-mitochondrial enzyme complex involved in the breakdown of the branched-chain amino acids isoleucine, leucine, and valine. The BCKD complex is thought to be composed of a core of 24 transacylase (E2) subunits, and associated decarboxylase (E1), dehydrogenase (E3), and regulatory subunits. This gene encodes the transacylase (E2) subunit. Mutations in this gene result in maple syrup urine disease, type 2. Alternatively spliced transcript variants have been described, but their biological validity has not been determined. [provided by RefSeq, Jul 2008]

DBT links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PM1

In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_001918.5

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.972

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DBT	NM_001918.5 linkuse as main transcript	c.1217G>T	p.Gly406Val	missense_variant	10/11	ENST00000370132.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
DBT	ENST00000370132.8 linkuse as main transcript	c.1217G>T	p.Gly406Val	missense_variant	10/11	1	NM_001918.5	P1
DBT	ENST00000681617.1 linkuse as main transcript	c.1343G>T	p.Gly448Val	missense_variant	11/12
DBT	ENST00000681780.1 linkuse as main transcript	c.674G>T	p.Gly225Val	missense_variant	11/12

Frequencies

GnomAD3 genomes

AF:

0.00000669

AC:

AN:

149438

Hom.:

Cov.:

show subpopulations

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:

0.0000148

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000799

AC:

AN:

250388

Hom.:

AF XY:

0.00000738

AC XY:

AN XY:

135532

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000199

AC:

AN:

1458688

Hom.:

Cov.:

AF XY:

0.0000165

AC XY:

AN XY:

725932

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000252

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000669

AC:

AN:

149438

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

72722

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000148

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Maple syrup urine disease

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Aug 31, 2021	This sequence change replaces glycine with valine at codon 406 of the DBT protein (p.Gly406Val). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and valine. This variant is present in population databases (rs767154711, ExAC 0.003%). This variant has not been reported in the literature in individuals affected with DBT-related conditions. 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: "Deleterious"; PolyPhen-2: "Probably Damaging"; 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. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Aug 28, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.95

BayesDel_addAF

Pathogenic

0.28

BayesDel_noAF

Pathogenic

0.17

Cadd

Pathogenic

Dann

Uncertain

1.0

Eigen

Pathogenic

0.86

Eigen_PC

Pathogenic

0.84

FATHMM_MKL

Pathogenic

1.0

M_CAP

Benign

0.028

MetaRNN

Pathogenic

0.97

MetaSVM

Benign

-0.68

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.71

PROVEAN

Pathogenic

-8.5

REVEL

Uncertain

0.58

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0020

Vest4

0.98

MutPred

0.87

Loss of ubiquitination at K410 (P = 0.1306);

MVP

0.80

MPC

1.2

ClinPred

1.0

GERP RS

6.0

gMVP

0.98

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over