rs1553230703

Positions:

• chr1-100214968-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_001918.5(DBT):​c.788T>C​(p.Met263Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,459,154 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M263V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: DBT NM_001918.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 8.95

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 Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.917
• PP5: Variant 1-100214968-A-G is Pathogenic according to our data. Variant chr1-100214968-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 552494.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DBT	NM_001918.5	c.788T>C	p.Met263Thr	missense_variant	7/11	ENST00000370132.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DBT	ENST00000370132.8	c.788T>C	p.Met263Thr	missense_variant	7/11	1	NM_001918.5	P1
DBT	ENST00000370131.3	c.788T>C	p.Met263Thr	missense_variant	7/8	1
DBT	ENST00000681617.1	c.788T>C	p.Met263Thr	missense_variant	7/12
DBT	ENST00000681780.1	c.245T>C	p.Met82Thr	missense_variant	8/12

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1459154 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 726144

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: 0.0000187

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Maple syrup urine disease Pathogenic:1 Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jul 25, 2022	Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt DBT protein function. ClinVar contains an entry for this variant (Variation ID: 552494). This missense change has been observed in individual(s) with maple syrup urine disease (PMID: 16786533). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 263 of the DBT protein (p.Met263Thr). This variant disrupts the p.Met263 amino acid residue in DBT. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19480318). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Jun 21, 2017	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Uncertain	25
DANN	Uncertain	0.99
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Benign	0.034	D
MetaRNN	Pathogenic	0.92	D;D
MetaSVM	Benign	-0.77	T
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-5.8	D;D
REVEL	Pathogenic	0.77
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Vest4		0.94
MutPred		0.78		Loss of stability (P = 0.0377);Loss of stability (P = 0.0377);
MVP		0.65
MPC		1.1
ClinPred		1.0	D
GERP RS		5.3
gMVP		0.81

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: rs1553230703; hg19: chr1-100680524;