NM_001918.5:c.1210-4dupA

Variant names:

• chr1-100206304-A-AT
• rs201117345
• NM_001918.5:c.1210-4dupA

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP6_Moderate

The NM_001918.5(DBT):​c.1210-4dupA variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000425 in 1,436,184 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.000027 (0 hom., cov: 30)
  • Exomes 𝑓: 0.00047 (0 hom.)
• Consequence: DBT NM_001918.5 splice_region, intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.564
• Publications: 2 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: ClinGen, Labcorp Genetics (formerly Invitae)
• maple syrup urine disease type 2

  Inheritance: AR Classification: DEFINITIVE Submitted by: G2P, Myriad Women’s Health
• 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: Likely_benign. The variant received -2 ACMG points.

• BP6: Variant 1-100206304-A-AT is Benign according to our data. Variant chr1-100206304-A-AT is described in ClinVar as Benign. ClinVar VariationId is 457145.Status of the report is criteria_provided_single_submitter, 1 stars.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DBT	NM_001918.5	MANE Select	c.1210-4dupA		splice_region intron	N/A	NP_001909.4	P11182
	DBT	NM_001399969.1		c.667-4dupA		splice_region intron	N/A	NP_001386898.1	A0A7P0T9W1
	DBT	NM_001399972.1		c.667-4dupA		splice_region intron	N/A	NP_001386901.1	A0A7P0T9W1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DBT	ENST00000370132.8	TSL:1 MANE Select	c.1210-4_1210-3insA		splice_region intron	N/A	ENSP00000359151.3	P11182
	DBT	ENST00000681617.1		c.1336-4_1336-3insA		splice_region intron	N/A	ENSP00000505544.1	A0A7P0Z494
	DBT	ENST00000875462.1		c.1210-4_1210-3insA		splice_region intron	N/A	ENSP00000545521.1

Frequencies

GnomAD3 genomes AF: 0.0000269 AC: 4 AN: 148698 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000595

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000302 AC: 59 AN: 195454 AF XY: 0.000416

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000333

Gnomad ASJ exome AF: 0.000245

Gnomad EAS exome AF: 0.000127

Gnomad FIN exome AF: 0.000621

Gnomad NFE exome AF: 0.000209

Gnomad OTH exome AF: 0.000620

GnomAD4 exome AF: 0.000471 AC: 607 AN: 1287388 Hom.: 0 Cov.: 29 AF XY: 0.000484 AC XY: 311 AN XY: 642856

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000219 AC: 7 AN: 31920

American (AMR) AF: 0.000126 AC: 5 AN: 39622

Ashkenazi Jewish (ASJ) AF: 0.000557 AC: 13 AN: 23352

East Asian (EAS) AF: 0.000137 AC: 5 AN: 36428

South Asian (SAS) AF: 0.000482 AC: 38 AN: 78870

European-Finnish (FIN) AF: 0.000362 AC: 17 AN: 46922

Middle Eastern (MID) AF: 0.000375 AC: 2 AN: 5334

European-Non Finnish (NFE) AF: 0.000510 AC: 495 AN: 971184

Other (OTH) AF: 0.000465 AC: 25 AN: 53756

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000269 AC: 4 AN: 148796 Hom.: 0 Cov.: 30 AF XY: 0.0000414 AC XY: 3 AN XY: 72550

African (AFR) AF: 0.00 AC: 0 AN: 40386

American (AMR) AF: 0.00 AC: 0 AN: 14874

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3430

East Asian (EAS) AF: 0.00 AC: 0 AN: 5128

South Asian (SAS) AF: 0.00 AC: 0 AN: 4706

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9852

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 288

European-Non Finnish (NFE) AF: 0.0000596 AC: 4 AN: 67164

Other (OTH) AF: 0.00 AC: 0 AN: 2066

Alfa AF: 0.000862 Hom.: 5

Bravo AF: 0.0000302

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Maple syrup urine disease (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.56
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs201117345; hg19: chr1-100671860;