rs115696850

Variant names:

• chr1-100206199-A-C
• rs115696850
• NM_001918.5:c.1281+31T>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001918.5(DBT):​c.1281+31T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0396 in 1,508,738 control chromosomes in the GnomAD database, including 1,466 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.030 (92 hom., cov: 30)
  • Exomes 𝑓: 0.041 (1374 hom.)
• Consequence: DBT NM_001918.5 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 2.52
• Publications: 7 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=-0.81).
• BP6: Variant 1-100206199-A-C is Benign according to our data. Variant chr1-100206199-A-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 93989.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0299 (4545/152060) while in subpopulation NFE AF = 0.0449 (3054/67992). AF 95% confidence interval is 0.0436. There are 92 homozygotes in GnomAd4. There are 2169 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 92 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001918.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DBT	NM_001918.5	MANE Select	c.1281+31T>G		intron	N/A	NP_001909.4
	DBT	NM_001399969.1		c.738+31T>G		intron	N/A	NP_001386898.1
	DBT	NM_001399972.1		c.738+31T>G		intron	N/A	NP_001386901.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DBT	ENST00000370132.8	TSL:1 MANE Select	c.1281+31T>G		intron	N/A	ENSP00000359151.3
	DBT	ENST00000681617.1		c.1407+31T>G		intron	N/A	ENSP00000505544.1
	DBT	ENST00000681780.1		c.738+31T>G		intron	N/A	ENSP00000505780.1

Frequencies

GnomAD3 genomes AF: 0.0299 AC: 4545 AN: 151944 Hom.: 92 Cov.: 30

Gnomad AFR AF: 0.00805

Gnomad AMI AF: 0.0363

Gnomad AMR AF: 0.0247

Gnomad ASJ AF: 0.0484

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0114

Gnomad FIN AF: 0.0438

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0449

Gnomad OTH AF: 0.0268

GnomAD2 exomes AF: 0.0317 AC: 7869 AN: 248570 AF XY: 0.0330

Gnomad AFR exome AF: 0.00697

Gnomad AMR exome AF: 0.0181

Gnomad ASJ exome AF: 0.0423

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0432

Gnomad NFE exome AF: 0.0465

Gnomad OTH exome AF: 0.0347

GnomAD4 exome AF: 0.0407 AC: 55213 AN: 1356678 Hom.: 1374 Cov.: 20 AF XY: 0.0401 AC XY: 27293 AN XY: 680782

African (AFR) AF: 0.00725 AC: 227 AN: 31292

American (AMR) AF: 0.0189 AC: 832 AN: 44130

Ashkenazi Jewish (ASJ) AF: 0.0419 AC: 1069 AN: 25492

East Asian (EAS) AF: 0.0000255 AC: 1 AN: 39190

South Asian (SAS) AF: 0.0104 AC: 866 AN: 83012

European-Finnish (FIN) AF: 0.0433 AC: 2308 AN: 53304

Middle Eastern (MID) AF: 0.0447 AC: 249 AN: 5566

European-Non Finnish (NFE) AF: 0.0468 AC: 47637 AN: 1017858

Other (OTH) AF: 0.0356 AC: 2024 AN: 56834

GnomAD4 genome AF: 0.0299 AC: 4545 AN: 152060 Hom.: 92 Cov.: 30 AF XY: 0.0292 AC XY: 2169 AN XY: 74342

African (AFR) AF: 0.00803 AC: 333 AN: 41476

American (AMR) AF: 0.0246 AC: 376 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.0484 AC: 168 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.0114 AC: 55 AN: 4820

European-Finnish (FIN) AF: 0.0438 AC: 462 AN: 10552

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.0449 AC: 3054 AN: 67992

Other (OTH) AF: 0.0266 AC: 56 AN: 2108

Alfa AF: 0.0360 Hom.: 16

Bravo AF: 0.0290

Asia WGS AF: 0.00549 AC: 19 AN: 3476

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Aug 23, 2013

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Jun 23, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Maple syrup urine disease Benign:1

Apr 11, 2023

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	6.4
DANN	Benign	0.80
PhyloP100		2.5
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs115696850; hg19: chr1-100671755;