rs72973763

Positions:

• chr1-100216040-T-C
• chr1-100216040-T-G

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.715A>G​(p.Ile239Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00595 in 1,613,626 control chromosomes in the GnomAD database, including 535 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I239L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.032 (283 hom., cov: 32)
  • Exomes 𝑓: 0.0033 (252 hom.)
• Consequence: DBT NM_001918.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.0790

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017527044).
• BP6: Variant 1-100216040-T-C is Benign according to our data. Variant chr1-100216040-T-C is described in ClinVar as [Benign]. Clinvar id is 94010.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-100216040-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.109 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DBT	NM_001918.5	c.715A>G	p.Ile239Val	missense_variant	6/11	ENST00000370132.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DBT	ENST00000370132.8	c.715A>G	p.Ile239Val	missense_variant	6/11	1	NM_001918.5	P1
DBT	ENST00000370131.3	c.715A>G	p.Ile239Val	missense_variant	6/8	1
DBT	ENST00000681617.1	c.715A>G	p.Ile239Val	missense_variant	6/12
DBT	ENST00000681780.1	c.172A>G	p.Ile58Val	missense_variant	7/12

Frequencies

GnomAD3 genomes AF: 0.0316 AC: 4804 AN: 152096 Hom.: 284 Cov.: 32

Gnomad AFR AF: 0.111

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00838

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.0239

GnomAD3 exomes AF: 0.00833 AC: 2094 AN: 251468 Hom.: 110 AF XY: 0.00611 AC XY: 831 AN XY: 135910

Gnomad AFR exome AF: 0.116

Gnomad AMR exome AF: 0.00434

Gnomad ASJ exome AF: 0.00149

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000167

Gnomad OTH exome AF: 0.00342

GnomAD4 exome AF: 0.00327 AC: 4780 AN: 1461412 Hom.: 252 Cov.: 30 AF XY: 0.00283 AC XY: 2056 AN XY: 727060

Gnomad4 AFR exome AF: 0.116

Gnomad4 AMR exome AF: 0.00479

Gnomad4 ASJ exome AF: 0.00149

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000243

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000143

Gnomad4 OTH exome AF: 0.00736

GnomAD4 genome AF: 0.0316 AC: 4816 AN: 152214 Hom.: 283 Cov.: 32 AF XY: 0.0307 AC XY: 2286 AN XY: 74428

Gnomad4 AFR AF: 0.111

Gnomad4 AMR AF: 0.00837

Gnomad4 ASJ AF: 0.000577

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000176

Gnomad4 OTH AF: 0.0237

Alfa AF: 0.00427 Hom.: 51

Bravo AF: 0.0368

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.112 AC: 492

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.0104 AC: 1258

Asia WGS AF: 0.0110 AC: 38 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.000237

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Maple syrup urine disease Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 08, 2015	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 23, 2013	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.055
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	0.43
DANN	Benign	0.58
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.086	N
MetaRNN	Benign	0.0018	T;T
MetaSVM	Benign	-0.96	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.23	T
PROVEAN	Benign	0.16	N;N
REVEL	Benign	0.029
Sift	Benign	1.0	T;T
Sift4G	Benign	0.58	T;T
Vest4		0.18
MPC		0.27
ClinPred		0.0072	T
GERP RS		0.65
gMVP		0.25

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: rs72973763; hg19: chr1-100681596; COSMIC: COSV64495090; COSMIC: COSV64495090;