1-100206304-ATT-AT

Position:

• chr1-100206304-ATT-AT

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_001918.5(DBT):​c.1210-4del variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0252 in 1,367,896 control chromosomes in the GnomAD database, including 29 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0031 (2 hom., cov: 30)
  • Exomes 𝑓: 0.028 (27 hom.)
• Consequence: DBT NM_001918.5 splice_region, splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.564

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 -16 ACMG points.

• BP6: Variant 1-100206304-AT-A is Benign according to our data. Variant chr1-100206304-AT-A is described in ClinVar as [Benign]. Clinvar id is 166981.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-100206304-AT-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0031 (461/148752) while in subpopulation AFR AF= 0.00849 (343/40380). AF 95% confidence interval is 0.00775. There are 2 homozygotes in gnomad4. There are 244 alleles in male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DBT	NM_001918.5	c.1210-4del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000370132.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DBT	ENST00000370132.8	c.1210-4del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_001918.5	P1
DBT	ENST00000681617.1	c.1336-4del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant
DBT	ENST00000681780.1	c.667-4del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant

Frequencies

GnomAD3 genomes AF: 0.00309 AC: 459 AN: 148654 Hom.: 2 Cov.: 30

Gnomad AFR AF: 0.00847

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00263

Gnomad ASJ AF: 0.000583

Gnomad EAS AF: 0.000584

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00264

Gnomad MID AF: 0.00645

Gnomad NFE AF: 0.000640

Gnomad OTH AF: 0.00146

GnomAD4 exome AF: 0.0279 AC: 33971 AN: 1219144 Hom.: 27 Cov.: 29 AF XY: 0.0271 AC XY: 16463 AN XY: 607688

Gnomad4 AFR exome AF: 0.0120

Gnomad4 AMR exome AF: 0.0422

Gnomad4 ASJ exome AF: 0.0224

Gnomad4 EAS exome AF: 0.0149

Gnomad4 SAS exome AF: 0.0211

Gnomad4 FIN exome AF: 0.0280

Gnomad4 NFE exome AF: 0.0291

Gnomad4 OTH exome AF: 0.0266

GnomAD4 genome AF: 0.00310 AC: 461 AN: 148752 Hom.: 2 Cov.: 30 AF XY: 0.00336 AC XY: 244 AN XY: 72526

Gnomad4 AFR AF: 0.00849

Gnomad4 AMR AF: 0.00262

Gnomad4 ASJ AF: 0.000583

Gnomad4 EAS AF: 0.000585

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00264

Gnomad4 NFE AF: 0.000640

Gnomad4 OTH AF: 0.00145

ClinVar

Significance: Benign

Submissions summary: Benign:6

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 29, 2024	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
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	Mar 12, 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)	Feb 10, 2014	- -

Maple syrup urine disease type 1A Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Nov 29, 2023

- -

Computational scores

Source: dbNSFP v4.3

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: rs201117345; hg19: chr1-100671860;