chr1-100224566-T-C

Variant names:

• chr1-100224566-T-C
• rs4143055
• NM_001918.5:c.434-5819A>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.434-5819A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.752 in 151,854 control chromosomes in the GnomAD database, including 45,438 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 0.75 (45438 hom., cov: 32)
• Consequence: DBT NM_001918.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0640
• Publications: 2 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=-0.9).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.929 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DBT	NM_001918.5	c.434-5819A>G		intron_variant	Intron 4 of 10	ENST00000370132.8	NP_001909.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DBT	ENST00000370132.8	c.434-5819A>G		intron_variant	Intron 4 of 10	1	NM_001918.5	ENSP00000359151.3

Frequencies

GnomAD3 genomes AF: 0.752 AC: 114109 AN: 151736 Hom.: 45424 Cov.: 32

Gnomad AFR AF: 0.461

Gnomad AMI AF: 0.803

Gnomad AMR AF: 0.854

Gnomad ASJ AF: 0.891

Gnomad EAS AF: 0.951

Gnomad SAS AF: 0.897

Gnomad FIN AF: 0.899

Gnomad MID AF: 0.859

Gnomad NFE AF: 0.849

Gnomad OTH AF: 0.784

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

GnomAD4 genome AF: 0.752 AC: 114155 AN: 151854 Hom.: 45438 Cov.: 32 AF XY: 0.759 AC XY: 56365 AN XY: 74252

African (AFR) AF: 0.460 AC: 19052 AN: 41394

American (AMR) AF: 0.855 AC: 13047 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.891 AC: 3088 AN: 3466

East Asian (EAS) AF: 0.951 AC: 4924 AN: 5178

South Asian (SAS) AF: 0.897 AC: 4324 AN: 4820

European-Finnish (FIN) AF: 0.899 AC: 9490 AN: 10552

Middle Eastern (MID) AF: 0.869 AC: 252 AN: 290

European-Non Finnish (NFE) AF: 0.848 AC: 57589 AN: 67872

Other (OTH) AF: 0.787 AC: 1660 AN: 2108

Alfa AF: 0.747 Hom.: 5431

Bravo AF: 0.738

Asia WGS AF: 0.874 AC: 3041 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	4.1
DANN	Benign	0.63
PhyloP100		0.064
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: rs4143055; hg19: chr1-100690122;