NM_001918.5:c.*5546G>A

Variant names:

• chr1-100190709-C-T
• rs11166412
• NM_001918.5:c.*5546G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001918.5(DBT):​c.*5546G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.791 in 152,008 control chromosomes in the GnomAD database, including 49,104 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.79 (49095 hom., cov: 31)
  • Exomes 𝑓: 1.0 (9 hom.)
• Consequence: DBT NM_001918.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.753
• Publications: 6 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BP6: Variant 1-100190709-C-T is Benign according to our data. Variant chr1-100190709-C-T is described in ClinVar as Benign. ClinVar VariationId is 291404.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.93 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DBT	NM_001918.5	c.*5546G>A		3_prime_UTR_variant	Exon 11 of 11	ENST00000370132.8	NP_001909.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DBT	ENST00000370132.8	c.*5546G>A		3_prime_UTR_variant	Exon 11 of 11	1	NM_001918.5	ENSP00000359151.3
ENSG00000285530	ENST00000835180.1	n.139+23766C>T		intron_variant	Intron 2 of 4

Frequencies

GnomAD3 genomes AF: 0.792 AC: 120225 AN: 151872 Hom.: 49079 Cov.: 31

Gnomad AFR AF: 0.564

Gnomad AMI AF: 0.805

Gnomad AMR AF: 0.876

Gnomad ASJ AF: 0.898

Gnomad EAS AF: 0.952

Gnomad SAS AF: 0.899

Gnomad FIN AF: 0.909

Gnomad MID AF: 0.880

Gnomad NFE AF: 0.865

Gnomad OTH AF: 0.819

GnomAD4 exome AF: 1.00 AC: 18 AN: 18 Hom.: 9 Cov.: 0 AF XY: 1.00 AC XY: 12 AN XY: 12

African (AFR) AF: 1.00 AC: 2 AN: 2

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 1.00 AC: 2 AN: 2

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 1.00 AC: 10 AN: 10

Other (OTH) AF: 1.00 AC: 4 AN: 4

GnomAD4 genome AF: 0.791 AC: 120279 AN: 151990 Hom.: 49095 Cov.: 31 AF XY: 0.797 AC XY: 59191 AN XY: 74276

African (AFR) AF: 0.564 AC: 23307 AN: 41322

American (AMR) AF: 0.876 AC: 13377 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.898 AC: 3117 AN: 3472

East Asian (EAS) AF: 0.952 AC: 4928 AN: 5176

South Asian (SAS) AF: 0.899 AC: 4338 AN: 4826

European-Finnish (FIN) AF: 0.909 AC: 9637 AN: 10600

Middle Eastern (MID) AF: 0.888 AC: 261 AN: 294

European-Non Finnish (NFE) AF: 0.865 AC: 58845 AN: 68004

Other (OTH) AF: 0.821 AC: 1738 AN: 2116

Alfa AF: 0.848 Hom.: 92245

Bravo AF: 0.779

Asia WGS AF: 0.882 AC: 3068 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Maple syrup urine disease Benign:2

Apr 11, 2023

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Jun 29, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.18
DANN	Benign	0.47
PhyloP100		-0.75
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: rs11166412; hg19: chr1-100656265;