1-100235416-CT-CTT

Variant names:

• chr1-100235416-C-CT
• rs201469612
• NM_001918.5:c.251+19dupA

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.251+19dupA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00897 in 1,272,154 control chromosomes in the GnomAD database, including 76 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0084 (11 hom., cov: 32)
  • Exomes 𝑓: 0.0090 (65 hom.)
• Consequence: DBT NM_001918.5 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -4.06
• Publications: 1 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: Labcorp Genetics (formerly Invitae), ClinGen
• maple syrup urine disease type 2

  Inheritance: AR Classification: DEFINITIVE Submitted by: Myriad Women’s Health, G2P
• 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 1-100235416-C-CT is Benign according to our data. Variant chr1-100235416-C-CT is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 93998.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 = 0.00844 (1283/152046) while in subpopulation NFE AF = 0.0134 (911/67942). AF 95% confidence interval is 0.0127. There are 11 homozygotes in GnomAd4. There are 599 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 11 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DBT	NM_001918.5	MANE Select	c.251+19dupA		intron	N/A	NP_001909.4
	DBT	NM_001399969.1		c.-293+19dupA		intron	N/A	NP_001386898.1
	DBT	NM_001399972.1		c.-293+19dupA		intron	N/A	NP_001386901.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DBT	ENST00000370132.8	TSL:1 MANE Select	c.251+19_251+20insA		intron	N/A	ENSP00000359151.3
	DBT	ENST00000370131.3	TSL:1	c.251+19_251+20insA		intron	N/A	ENSP00000359150.3
	DBT	ENST00000681617.1		c.251+19_251+20insA		intron	N/A	ENSP00000505544.1

Frequencies

GnomAD3 genomes AF: 0.00845 AC: 1284 AN: 151928 Hom.: 11 Cov.: 32

Gnomad AFR AF: 0.00186

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0100

Gnomad ASJ AF: 0.00751

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.00777

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0134

Gnomad OTH AF: 0.0101

GnomAD2 exomes AF: 0.00857 AC: 2110 AN: 246188 AF XY: 0.00876

Gnomad AFR exome AF: 0.00137

Gnomad AMR exome AF: 0.00462

Gnomad ASJ exome AF: 0.00726

Gnomad EAS exome AF: 0.0000554

Gnomad FIN exome AF: 0.00857

Gnomad NFE exome AF: 0.0137

Gnomad OTH exome AF: 0.0107

GnomAD4 exome AF: 0.00904 AC: 10130 AN: 1120108 Hom.: 65 Cov.: 16 AF XY: 0.00916 AC XY: 5245 AN XY: 572618

African (AFR) AF: 0.00131 AC: 35 AN: 26730

American (AMR) AF: 0.00491 AC: 213 AN: 43398

Ashkenazi Jewish (ASJ) AF: 0.00706 AC: 168 AN: 23800

East Asian (EAS) AF: 0.0000265 AC: 1 AN: 37722

South Asian (SAS) AF: 0.00294 AC: 220 AN: 74836

European-Finnish (FIN) AF: 0.00927 AC: 488 AN: 52636

Middle Eastern (MID) AF: 0.00662 AC: 31 AN: 4686

European-Non Finnish (NFE) AF: 0.0106 AC: 8571 AN: 807426

Other (OTH) AF: 0.00825 AC: 403 AN: 48874

GnomAD4 genome AF: 0.00844 AC: 1283 AN: 152046 Hom.: 11 Cov.: 32 AF XY: 0.00806 AC XY: 599 AN XY: 74348

African (AFR) AF: 0.00186 AC: 77 AN: 41498

American (AMR) AF: 0.0100 AC: 153 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00751 AC: 26 AN: 3460

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00228 AC: 11 AN: 4816

European-Finnish (FIN) AF: 0.00777 AC: 82 AN: 10556

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0134 AC: 911 AN: 67942

Other (OTH) AF: 0.00995 AC: 21 AN: 2110

Alfa AF: 0.0139 Hom.: 10

Bravo AF: 0.00742

Asia WGS AF: 0.00231 AC: 8 AN: 3472

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-4.1
Mutation Taster		=100/0	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: rs201469612; hg19: chr1-100700972;