1-100206294-C-T

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1PM2PP3_Strong

The NM_001918.5(DBT):c.1217G>A(p.Gly406Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,458,688 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G406V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 30)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

DBT
NM_001918.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.48

Publications

1 publications found

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 Gene-Disease associations (from GenCC):

maple syrup urine disease
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen
maple syrup urine disease type 2
Inheritance: AR Classification: DEFINITIVE Submitted by: Myriad Women’s Health, G2P
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

DBT links:

ENSG00000285530 (HGNC:):

ENSG00000285530 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

PM1

In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_001918.5

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.979

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DBT	NM_001918.5 link	c.1217G>A	p.Gly406Asp	missense_variant	Exon 10 of 11	ENST00000370132.8	NP_001909.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
DBT	ENST00000370132.8 link	c.1217G>A	p.Gly406Asp	missense_variant	Exon 10 of 11	1	NM_001918.5	ENSP00000359151.3
DBT	ENST00000681617.1 link	c.1343G>A	p.Gly448Asp	missense_variant	Exon 11 of 12			ENSP00000505544.1
DBT	ENST00000681780.1 link	c.674G>A	p.Gly225Asp	missense_variant	Exon 11 of 12			ENSP00000505780.1
ENSG00000285530	ENST00000835180.1 link	n.140-12350C>T		intron_variant	Intron 2 of 4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000399

AC:

AN:

250388

AF XY:

0.00000738

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.86e-7

AC:

AN:

1458688

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

725932

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33390

American (AMR)

AF:

0.0000224

AC:

AN:

44630

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26088

East Asian (EAS)

AF:

0.00

AC:

AN:

39674

South Asian (SAS)

AF:

0.00

AC:

AN:

86000

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53308

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1109558

Other (OTH)

AF:

0.00

AC:

AN:

60276

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.26

BayesDel_noAF

Pathogenic

0.21

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.99

FATHMM_MKL

Pathogenic

1.0

M_CAP

Benign

0.042

MetaRNN

Pathogenic

0.98

MetaSVM

Uncertain

0.34

PhyloP100

7.5

PrimateAI

Uncertain

0.77

PROVEAN

Pathogenic

-6.7

REVEL

Pathogenic

0.67

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0010

Vest4

0.99

MutPred

0.90

Gain of ubiquitination at K410 (P = 0.0633);

MVP

0.90

MPC

1.2

ClinPred

1.0

GERP RS

6.0

gMVP

0.99

Mutation Taster

=13/87

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over