chr1-100198123-T-C

Variant names:

• chr1-100198123-T-C
• rs2810424
• NM_001918.5:c.1282-1701A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001918.5(DBT):​c.1282-1701A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.875 in 152,228 control chromosomes in the GnomAD database, including 58,619 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.87 (58619 hom., cov: 32)
• Consequence: DBT NM_001918.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.09
• Publications: 8 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: 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

ENSG00000285530 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.0).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.943 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DBT	NM_001918.5	MANE Select	c.1282-1701A>G		intron	N/A	NP_001909.4
	DBT	NM_001399969.1		c.739-1701A>G		intron	N/A	NP_001386898.1
	DBT	NM_001399972.1		c.739-1701A>G		intron	N/A	NP_001386901.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DBT	ENST00000370132.8	TSL:1 MANE Select	c.1282-1701A>G		intron	N/A	ENSP00000359151.3
	DBT	ENST00000681617.1		c.1408-1701A>G		intron	N/A	ENSP00000505544.1
	DBT	ENST00000681780.1		c.739-1701A>G		intron	N/A	ENSP00000505780.1

Frequencies

GnomAD3 genomes AF: 0.875 AC: 133097 AN: 152110 Hom.: 58594 Cov.: 32

Gnomad AFR AF: 0.762

Gnomad AMI AF: 0.852

Gnomad AMR AF: 0.916

Gnomad ASJ AF: 0.913

Gnomad EAS AF: 0.965

Gnomad SAS AF: 0.953

Gnomad FIN AF: 0.934

Gnomad MID AF: 0.908

Gnomad NFE AF: 0.911

Gnomad OTH AF: 0.889

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

GnomAD4 genome AF: 0.875 AC: 133171 AN: 152228 Hom.: 58619 Cov.: 32 AF XY: 0.879 AC XY: 65409 AN XY: 74440

African (AFR) AF: 0.761 AC: 31602 AN: 41508

American (AMR) AF: 0.917 AC: 14009 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.913 AC: 3167 AN: 3470

East Asian (EAS) AF: 0.965 AC: 5005 AN: 5186

South Asian (SAS) AF: 0.952 AC: 4598 AN: 4830

European-Finnish (FIN) AF: 0.934 AC: 9903 AN: 10604

Middle Eastern (MID) AF: 0.912 AC: 268 AN: 294

European-Non Finnish (NFE) AF: 0.911 AC: 61963 AN: 68030

Other (OTH) AF: 0.891 AC: 1881 AN: 2112

Alfa AF: 0.905 Hom.: 30958

Bravo AF: 0.868

Asia WGS AF: 0.925 AC: 3216 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.27
DANN	Benign	0.63
PhyloP100		-2.1
Mutation Taster		=100/0	polymorphism (auto)

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: rs2810424; hg19: chr1-100663679;