rs146249007

chr1-100216031-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001918.5(DBT):c.724T>C(p.Ser242Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00947 in 1,613,176 control chromosomes in the GnomAD database, including 90 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0084 (11 hom., cov: 32)
  • Exomes 𝑓: 0.0096 (79 hom.)
• Consequence: DBT NM_001918.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 0.899

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=0.0040974617).
• BP6: Variant 1-100216031-A-G is Benign according to our data. Variant chr1-100216031-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 94011.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-100216031-A-G is described in Lovd as [Benign]. Variant chr1-100216031-A-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00841 (1280/152134) while in subpopulation NFE AF= 0.0134 (908/68000). AF 95% confidence interval is 0.0126. There are 11 homozygotes in gnomad4. There are 599 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 11 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DBT	NM_001918.5	c.724T>C	p.Ser242Pro	missense_variant	6/11	ENST00000370132.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DBT	ENST00000370132.8	c.724T>C	p.Ser242Pro	missense_variant	6/11	1	NM_001918.5	P1
DBT	ENST00000370131.3	c.724T>C	p.Ser242Pro	missense_variant	6/8	1
DBT	ENST00000681617.1	c.724T>C	p.Ser242Pro	missense_variant	6/12
DBT	ENST00000681780.1	c.181T>C	p.Ser61Pro	missense_variant	7/12

Frequencies

GnomAD3 genomes AF: 0.00843 AC: 1281 AN: 152016 Hom.: 11 Cov.: 32

Gnomad AFR AF: 0.00184

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0100

Gnomad ASJ AF: 0.00749

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.00795

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0134

Gnomad OTH AF: 0.0100

GnomAD3 exomes AF: 0.00855 AC: 2151 AN: 251452 Hom.: 17 AF XY: 0.00872 AC XY: 1185 AN XY: 135900

Gnomad AFR exome AF: 0.00135

Gnomad AMR exome AF: 0.00471

Gnomad ASJ exome AF: 0.00754

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00258

Gnomad FIN exome AF: 0.00818

Gnomad NFE exome AF: 0.0138

Gnomad OTH exome AF: 0.0109

GnomAD4 exome AF: 0.00958 AC: 13993 AN: 1461042 Hom.: 79 Cov.: 30 AF XY: 0.00965 AC XY: 7018 AN XY: 726934

Gnomad4 AFR exome AF: 0.00131

Gnomad4 AMR exome AF: 0.00508

Gnomad4 ASJ exome AF: 0.00781

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00301

Gnomad4 FIN exome AF: 0.00891

Gnomad4 NFE exome AF: 0.0110

Gnomad4 OTH exome AF: 0.00868

GnomAD4 genome AF: 0.00841 AC: 1280 AN: 152134 Hom.: 11 Cov.: 32 AF XY: 0.00806 AC XY: 599 AN XY: 74348

Gnomad4 AFR AF: 0.00183

Gnomad4 AMR AF: 0.0100

Gnomad4 ASJ AF: 0.00749

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00228

Gnomad4 FIN AF: 0.00795

Gnomad4 NFE AF: 0.0134

Gnomad4 OTH AF: 0.00993

Alfa AF: 0.0112 Hom.: 20

Bravo AF: 0.00740

TwinsUK AF: 0.00836 AC: 31

ALSPAC AF: 0.0127 AC: 49

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.0103 AC: 89

ExAC AF: 0.00959 AC: 1165

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.0118

EpiControl AF: 0.0117

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Maple syrup urine disease Benign:5

Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Nov 05, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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. -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Sep 06, 2016	- -

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 23, 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)	Oct 30, 2013	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2023	DBT: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jun 04, 2015	- -

Maple syrup urine disease type 1A Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Sep 21, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.66
Cadd	Benign	9.6
Dann	Benign	0.84
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.99
FATHMM_MKL	Benign	0.35	N
MetaRNN	Benign	0.0041	T;T
MetaSVM	Benign	-0.95	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	0.0	N;N
REVEL	Benign	0.026
Sift	Benign	0.33	T;T
Sift4G	Benign	0.26	T;T
Vest4		0.25
MVP		0.18
MPC		0.53
ClinPred		0.00031	T
GERP RS		0.24
gMVP		0.54

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: rs146249007; hg19: chr1-100681587;