rs1553230841

Variant names:

• chr1-100216121-G-A
• rs1553230841
• NM_001918.5:c.634C>T

Your query was ambiguous. Multiple possible variants found:

• chr1-100216121-G-A
• chr1-100216121-G-T

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001918.5(DBT):​c.634C>T​(p.Gln212*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: DBT NM_001918.5 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 9.34
• Publications: 0 publications found

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: ClinGen, Labcorp Genetics (formerly Invitae)
• maple syrup urine disease type 2

  Inheritance: AR Classification: DEFINITIVE Submitted by: G2P, Myriad Women’s Health
• 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

ENSG00000285530 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-100216121-G-A is Pathogenic according to our data. Variant chr1-100216121-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 557560.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001918.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DBT	NM_001918.5	MANE Select	c.634C>T	p.Gln212*	stop_gained	Exon 6 of 11	NP_001909.4	P11182
	DBT	NM_001399969.1		c.91C>T	p.Gln31*	stop_gained	Exon 7 of 12	NP_001386898.1	A0A7P0T9W1
	DBT	NM_001399972.1		c.91C>T	p.Gln31*	stop_gained	Exon 7 of 12	NP_001386901.1	A0A7P0T9W1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DBT	ENST00000370132.8	TSL:1 MANE Select	c.634C>T	p.Gln212*	stop_gained	Exon 6 of 11	ENSP00000359151.3	P11182
	DBT	ENST00000370131.3	TSL:1	c.634C>T	p.Gln212*	stop_gained	Exon 6 of 8	ENSP00000359150.3	Q5VVL7
	DBT	ENST00000681617.1		c.634C>T	p.Gln212*	stop_gained	Exon 6 of 12	ENSP00000505544.1	A0A7P0Z494

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Maple syrup urine disease (2)
2	-	-	Maple syrup urine disease type 1A (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.66
CADD	Pathogenic	38
DANN	Uncertain	1.0
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.95
FATHMM_MKL	Pathogenic	0.99	D
PhyloP100		9.3
Vest4		0.99
GERP RS		5.7
Mutation Taster		=1/199	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1553230841; hg19: chr1-100681677;