1-100187700-ATTTTTTT-ATTTTTTTT

Variant names:

• chr1-100187700-A-AT
• rs886044938
• NM_001918.5:c.*8554dupA

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6 BA1

The NM_001918.5(DBT):​c.*8554dupA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0422 in 124,128 control chromosomes in the GnomAD database, including 267 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.042 (267 hom., cov: 31)
  • Failed GnomAD Quality Control
• Consequence: DBT NM_001918.5 3_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -1.50
• Publications: 0 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: Benign. The variant received -9 ACMG points.

• BP6: Variant 1-100187700-A-AT is Benign according to our data. Variant chr1-100187700-A-AT is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 291383.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.121 is higher than 0.05.

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.*8554dupA		3_prime_UTR	Exon 11 of 11	NP_001909.4	P11182
	DBT	NM_001399969.1		c.*8554dupA		3_prime_UTR	Exon 12 of 12	NP_001386898.1	A0A7P0T9W1
	DBT	NM_001399972.1		c.*8554dupA		3_prime_UTR	Exon 12 of 12	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.*8554dupA		3_prime_UTR	Exon 11 of 11	ENSP00000359151.3	P11182
	DBT	ENST00000875462.1		c.*42-4574dupA		intron	N/A	ENSP00000545521.1
	ENSG00000285530	ENST00000835180.1		n.139+20774dupT		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0421 AC: 5227 AN: 124144 Hom.: 267 Cov.: 31

Gnomad AFR AF: 0.124

Gnomad AMI AF: 0.00259

Gnomad AMR AF: 0.0350

Gnomad ASJ AF: 0.00740

Gnomad EAS AF: 0.00641

Gnomad SAS AF: 0.00423

Gnomad FIN AF: 0.00537

Gnomad MID AF: 0.0191

Gnomad NFE AF: 0.00802

Gnomad OTH AF: 0.0325

GnomAD4 exome Data not reliable, filtered out with message: AC0 AC: 0 AN: 0 Hom.: 0 Cov.: 0 AC XY: 0 AN XY: 0

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AC: 0 AN: 0

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.0421 AC: 5232 AN: 124128 Hom.: 267 Cov.: 31 AF XY: 0.0425 AC XY: 2539 AN XY: 59798

African (AFR) AF: 0.124 AC: 4176 AN: 33742

American (AMR) AF: 0.0351 AC: 434 AN: 12374

Ashkenazi Jewish (ASJ) AF: 0.00740 AC: 22 AN: 2974

East Asian (EAS) AF: 0.00643 AC: 27 AN: 4200

South Asian (SAS) AF: 0.00400 AC: 16 AN: 4002

European-Finnish (FIN) AF: 0.00537 AC: 37 AN: 6886

Middle Eastern (MID) AF: 0.0168 AC: 4 AN: 238

European-Non Finnish (NFE) AF: 0.00802 AC: 459 AN: 57210

Other (OTH) AF: 0.0318 AC: 55 AN: 1730

Alfa AF: 0.000285 Hom.: 1

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Maple syrup urine disease (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-1.5
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs886044938; hg19: chr1-100653256;