chr1-100206504-T-C

Position:

• chr1-100206504-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001918.5(DBT):​c.1150A>G​(p.Ser384Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.908 in 1,613,388 control chromosomes in the GnomAD database, including 665,858 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. S384S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.88 (58729 hom., cov: 31)
  • Exomes 𝑓: 0.91 (607129 hom.)
• Consequence: DBT NM_001918.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 1.94

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.0305434E-6).
• BP6: Variant 1-100206504-T-C is Benign according to our data. Variant chr1-100206504-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 128885.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-100206504-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.944 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DBT	NM_001918.5	c.1150A>G	p.Ser384Gly	missense_variant	9/11	ENST00000370132.8	NP_001909.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DBT	ENST00000370132.8	c.1150A>G	p.Ser384Gly	missense_variant	9/11	1	NM_001918.5	ENSP00000359151.3
DBT	ENST00000681617.1	c.1276A>G	p.Ser426Gly	missense_variant	10/12			ENSP00000505544.1
DBT	ENST00000681780.1	c.607A>G	p.Ser203Gly	missense_variant	10/12			ENSP00000505780.1

Frequencies

GnomAD3 genomes AF: 0.876 AC: 133222 AN: 152050 Hom.: 58703 Cov.: 31

Gnomad AFR AF: 0.765

Gnomad AMI AF: 0.852

Gnomad AMR AF: 0.917

Gnomad ASJ AF: 0.913

Gnomad EAS AF: 0.967

Gnomad SAS AF: 0.953

Gnomad FIN AF: 0.934

Gnomad MID AF: 0.908

Gnomad NFE AF: 0.911

Gnomad OTH AF: 0.890

GnomAD3 exomes AF: 0.917 AC: 230704 AN: 251468 Hom.: 106115 AF XY: 0.920 AC XY: 125056 AN XY: 135910

Gnomad AFR exome AF: 0.763

Gnomad AMR exome AF: 0.955

Gnomad ASJ exome AF: 0.917

Gnomad EAS exome AF: 0.969

Gnomad SAS exome AF: 0.952

Gnomad FIN exome AF: 0.931

Gnomad NFE exome AF: 0.908

Gnomad OTH exome AF: 0.913

GnomAD4 exome AF: 0.911 AC: 1331229 AN: 1461220 Hom.: 607129 Cov.: 43 AF XY: 0.913 AC XY: 663563 AN XY: 726956

Gnomad4 AFR exome AF: 0.763

Gnomad4 AMR exome AF: 0.951

Gnomad4 ASJ exome AF: 0.915

Gnomad4 EAS exome AF: 0.980

Gnomad4 SAS exome AF: 0.952

Gnomad4 FIN exome AF: 0.929

Gnomad4 NFE exome AF: 0.907

Gnomad4 OTH exome AF: 0.909

GnomAD4 genome AF: 0.876 AC: 133297 AN: 152168 Hom.: 58729 Cov.: 31 AF XY: 0.880 AC XY: 65449 AN XY: 74400

Gnomad4 AFR AF: 0.765

Gnomad4 AMR AF: 0.917

Gnomad4 ASJ AF: 0.913

Gnomad4 EAS AF: 0.967

Gnomad4 SAS AF: 0.952

Gnomad4 FIN AF: 0.934

Gnomad4 NFE AF: 0.911

Gnomad4 OTH AF: 0.891

Alfa AF: 0.907 Hom.: 111723

Bravo AF: 0.869

TwinsUK AF: 0.906 AC: 3361

ALSPAC AF: 0.907 AC: 3495

ESP6500AA AF: 0.775 AC: 3414

ESP6500EA AF: 0.902 AC: 7761

ExAC AF: 0.914 AC: 110942

Asia WGS AF: 0.926 AC: 3223 AN: 3478

EpiCase AF: 0.905

EpiControl AF: 0.904

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 03, 2021	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 24, 2015	- -

Maple syrup urine disease Benign:3

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 30, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jul 19, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 29306928, 14517957, 26232051, 27884173, 9621512, 20981092) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Maple syrup urine disease type 1A Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Nov 29, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.044
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	14
DANN	Benign	0.15
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.59
FATHMM_MKL	Benign	0.017	N
MetaRNN	Benign	0.0000010	T
MetaSVM	Benign	-1.0	T
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	3.0	N
REVEL	Benign	0.12
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Vest4		0.042
MPC		0.29
ClinPred		0.00015	T
GERP RS		4.4
gMVP		0.68

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: rs12021720; hg19: chr1-100672060;