rs201755806

Variant names:

• chr1-100206309-T-TA
• rs201755806
• NM_001918.5:c.1210-9_1210-8insT

Your query was ambiguous. Multiple possible variants found:

• chr1-100206309-T-TA
• chr1-100206309-T-TAA
• chr1-100206309-T-TAAA
• chr1-100206309-T-TAAAA
• chr1-100206309-T-TAAAAA

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP6_Moderate BS2

The NM_001918.5(DBT):​c.1210-9_1210-8insT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0173 in 1,394,356 control chromosomes in the GnomAD database, including 11 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., cov: 29)
  • Exomes 𝑓: 0.019 (11 hom.)
• Consequence: DBT NM_001918.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:3
• Conservation: PhyloP100: 0.732
• 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: Likely_benign. The variant received -6 ACMG points.

• BP6: Variant 1-100206309-T-TA is Benign according to our data. Variant chr1-100206309-T-TA is described in ClinVar as Benign. ClinVar VariationId is 457146.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAdExome4 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.1210-9_1210-8insT		intron	N/A	NP_001909.4
	DBT	NM_001399969.1		c.667-9_667-8insT		intron	N/A	NP_001386898.1
	DBT	NM_001399972.1		c.667-9_667-8insT		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.1210-9_1210-8insT		intron	N/A	ENSP00000359151.3
	DBT	ENST00000681617.1		c.1336-9_1336-8insT		intron	N/A	ENSP00000505544.1
	DBT	ENST00000681780.1		c.667-9_667-8insT		intron	N/A	ENSP00000505780.1

Frequencies

GnomAD3 genomes AF: 0.000188 AC: 28 AN: 148728 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000334

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000210

Gnomad FIN AF: 0.000845

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000208

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0117 AC: 2434 AN: 208398 AF XY: 0.0112

Gnomad AFR exome AF: 0.00152

Gnomad AMR exome AF: 0.0208

Gnomad ASJ exome AF: 0.0110

Gnomad EAS exome AF: 0.00481

Gnomad FIN exome AF: 0.0155

Gnomad NFE exome AF: 0.0121

Gnomad OTH exome AF: 0.0123

GnomAD4 exome AF: 0.0193 AC: 24056 AN: 1245526 Hom.: 11 Cov.: 29 AF XY: 0.0183 AC XY: 11378 AN XY: 621670

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

African (AFR) AF: 0.00274 AC: 87 AN: 31750

American (AMR) AF: 0.0212 AC: 791 AN: 37230

Ashkenazi Jewish (ASJ) AF: 0.0142 AC: 321 AN: 22634

East Asian (EAS) AF: 0.00958 AC: 340 AN: 35498

South Asian (SAS) AF: 0.0110 AC: 845 AN: 76508

European-Finnish (FIN) AF: 0.0172 AC: 785 AN: 45652

Middle Eastern (MID) AF: 0.00576 AC: 30 AN: 5206

European-Non Finnish (NFE) AF: 0.0212 AC: 19910 AN: 939162

Other (OTH) AF: 0.0183 AC: 947 AN: 51886

⚠️ 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: 0.000202 AC: 30 AN: 148830 Hom.: 0 Cov.: 29 AF XY: 0.000276 AC XY: 20 AN XY: 72452

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

African (AFR) AF: 0.0000246 AC: 1 AN: 40610

American (AMR) AF: 0.000401 AC: 6 AN: 14970

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3448

East Asian (EAS) AF: 0.00 AC: 0 AN: 5154

South Asian (SAS) AF: 0.000210 AC: 1 AN: 4754

European-Finnish (FIN) AF: 0.000845 AC: 8 AN: 9470

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000208 AC: 14 AN: 67160

Other (OTH) AF: 0.00 AC: 0 AN: 2066

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0167 Hom.: 1

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.73
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs201755806; hg19: chr1-100671865; COSMIC: COSV64496203; COSMIC: COSV64496203;