chr1-100206199-A-C

Position:

• chr1-100206199-A-C

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.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

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 (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 [Likely_benign]. Clinvar id 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 male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 92 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DBT	NM_001918.5	c.1281+31T>G		intron_variant		ENST00000370132.8	NP_001909.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DBT	ENST00000370132.8	c.1281+31T>G		intron_variant		1	NM_001918.5	ENSP00000359151	P1
DBT	ENST00000681617.1	c.1407+31T>G		intron_variant				ENSP00000505544
DBT	ENST00000681780.1	c.738+31T>G		intron_variant				ENSP00000505780

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

GnomAD3 exomes AF: 0.0317 AC: 7869 AN: 248570 Hom.: 186 AF XY: 0.0330 AC XY: 4422 AN XY: 134132

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 SAS exome AF: 0.0108

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

Gnomad4 AFR exome AF: 0.00725

Gnomad4 AMR exome AF: 0.0189

Gnomad4 ASJ exome AF: 0.0419

Gnomad4 EAS exome AF: 0.0000255

Gnomad4 SAS exome AF: 0.0104

Gnomad4 FIN exome AF: 0.0433

Gnomad4 NFE exome AF: 0.0468

Gnomad4 OTH exome AF: 0.0356

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

Gnomad4 AFR AF: 0.00803

Gnomad4 AMR AF: 0.0246

Gnomad4 ASJ AF: 0.0484

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0114

Gnomad4 FIN AF: 0.0438

Gnomad4 NFE AF: 0.0449

Gnomad4 OTH AF: 0.0266

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

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 23, 2013	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 23, 2018	- -

Maple syrup urine disease Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Apr 11, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	6.4
DANN	Benign	0.80

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

Publications

LitVar

Other links and lift over

dbSNP: rs115696850; hg19: chr1-100671755;