rs796052135

Positions:

• chr1-100207186-T-C

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PP3 PP5_Very_Strong

The NM_001918.5(DBT):​c.1018-550A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000329 in 152,190 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: 𝑓 0.000033 (0 hom., cov: 32)
• Consequence: DBT NM_001918.5 intron
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6 U:1
• Conservation: PhyloP100: -0.146

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]

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 1-100207186-T-C is Pathogenic according to our data. Variant chr1-100207186-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 11946.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DBT	NM_001918.5	c.1018-550A>G		intron_variant		ENST00000370132.8	NP_001909.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DBT	ENST00000370132.8	c.1018-550A>G		intron_variant		1	NM_001918.5	ENSP00000359151	P1
DBT	ENST00000681617.1	c.1144-550A>G		intron_variant				ENSP00000505544
DBT	ENST00000681780.1	c.475-550A>G		intron_variant				ENSP00000505780

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152190 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.0000441

Gnomad OTH AF: 0.00

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152190 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74350

Gnomad4 AFR AF: 0.00

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: 0.0000441

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000302

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Maple syrup urine disease Pathogenic:3 Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 27, 2021	Variant summary: DBT c.1018-550A>G is located at a deep intronic position, not widely known to affect splicing. Several computational tools predict a significant impact on normal splicing: three predict the variant creates a 5' donor site. The variant allele was found at a frequency of 3.3e-05 in 150962 control chromosomes (gnomAD v3.1 genomes dataset). c.1018-550A>G has been reported in the literature in a homozygous individual affected with Maple Syrup Urine Disease (Tsuruta_1998). The authors of this study reported experimental evidence and demonstrated that the level of the DBT protein was considerably decreased in patient derived LCLS, in addition, they found inclusion of intronic sequence in patient derived cDNA, which was predicted to result in a truncated protein. These findings were confirmed in an in vitro assay system, where generation of a pseudoexon was demonstrated, resulting in aberrant splicing in vitro (Tsuruta_1998). These data indicate that the variant is likely associated with disease. Two ClinVar submitters have assessed the variant since 2014,, and classified the variant as likely pathogenic or uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -
Uncertain significance, flagged submission	clinical testing	Counsyl	Jul 31, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 18, 2024	This sequence change falls in intron 8 of the DBT gene. It does not directly change the encoded amino acid sequence of the DBT protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with maple syrup urine disease (PMID: 9621512). ClinVar contains an entry for this variant (Variation ID: 11946). Studies have shown that this variant results in an insertion between exons 8 and 9 and introduces a premature termination codon (PMID: 9621512). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. -

Maple syrup urine disease type 2 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 1998

- -

DBT-related disorder Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 03, 2023

The DBT c.1018-550A>G variant is predicted to interfere with splicing. This variant was reported in the homozygous or compound heterozygous states in individuals with maple syrup urine disease (Tsuruta et al. 1998. PubMed ID: 9621512; Soriano-Sexto et al. PubMed ID: 36361642). In vitro analysis indicated that this substitution created a new 5' splice site and caused an insertion of 126 nucleotides between exons 8 and 9, resulting in a truncated protein (Tsuruta et al. 1998. PubMed ID: 9621512; Vorechovsky et al. 2010. PubMed ID: 19823873). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as likely pathogenic. -

Maple syrup urine disease type 1A Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Nov 29, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Pathogenic	27
DANN	Benign	0.67

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.79		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.79		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs796052135; hg19: chr1-100672742;