NM_001918.5:c.1210-4delA

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_001918.5(DBT):​c.1210-4delA variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0252 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, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• 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: Benign. The variant received -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 VariationId is 166981.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DBT	NM_001918.5	MANE Select	c.1210-4delA		splice_region intron	N/A	NP_001909.4	P11182
	DBT	NM_001399969.1		c.667-4delA		splice_region intron	N/A	NP_001386898.1	A0A7P0T9W1
	DBT	NM_001399972.1		c.667-4delA		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.1210-4delA		splice_region intron	N/A	ENSP00000359151.3	P11182
	DBT	ENST00000681617.1		c.1336-4delA		splice_region intron	N/A	ENSP00000505544.1	A0A7P0Z494
	DBT	ENST00000875462.1		c.1210-4delA		splice_region intron	N/A	ENSP00000545521.1

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

GnomAD2 exomes AF: 0.0311 AC: 6078 AN: 195454 AF XY: 0.0314

Gnomad AFR exome AF: 0.0116

Gnomad AMR exome AF: 0.0547

Gnomad ASJ exome AF: 0.0221

Gnomad EAS exome AF: 0.0119

Gnomad FIN exome AF: 0.0302

Gnomad NFE exome AF: 0.0339

Gnomad OTH exome AF: 0.0293

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

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

African (AFR) AF: 0.0120 AC: 378 AN: 31516

American (AMR) AF: 0.0422 AC: 1554 AN: 36822

Ashkenazi Jewish (ASJ) AF: 0.0224 AC: 495 AN: 22100

East Asian (EAS) AF: 0.0149 AC: 515 AN: 34560

South Asian (SAS) AF: 0.0211 AC: 1571 AN: 74442

European-Finnish (FIN) AF: 0.0280 AC: 1230 AN: 43930

Middle Eastern (MID) AF: 0.0131 AC: 68 AN: 5186

European-Non Finnish (NFE) AF: 0.0291 AC: 26807 AN: 919790

Other (OTH) AF: 0.0266 AC: 1353 AN: 50798

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

African (AFR) AF: 0.00849 AC: 343 AN: 40380

American (AMR) AF: 0.00262 AC: 39 AN: 14870

Ashkenazi Jewish (ASJ) AF: 0.000583 AC: 2 AN: 3428

East Asian (EAS) AF: 0.000585 AC: 3 AN: 5128

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

European-Finnish (FIN) AF: 0.00264 AC: 26 AN: 9836

Middle Eastern (MID) AF: 0.00694 AC: 2 AN: 288

European-Non Finnish (NFE) AF: 0.000640 AC: 43 AN: 67148

Other (OTH) AF: 0.00145 AC: 3 AN: 2066

Alfa AF: 0.0241 Hom.: 5

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Maple syrup urine disease (3)
-	-	2	not specified (2)
-	-	1	Maple syrup urine disease type 1A (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.56
Mutation Taster		=95/5	polymorphism

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: rs201117345; hg19: chr1-100671860; COSMIC: COSV64494912; COSMIC: COSV64494912;