rs201469612

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr1-100235416-CT-C
• chr1-100235416-CT-CTT

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001918.5(DBT):​c.251+19delA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000893 in 1,120,194 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 8.9e-7 (0 hom.)
• Consequence: DBT NM_001918.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -4.06
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.251+19delA		intron	N/A	NP_001909.4	P11182
	DBT	NM_001399969.1		c.-293+19delA		intron	N/A	NP_001386898.1	A0A7P0T9W1
	DBT	NM_001399972.1		c.-293+19delA		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.251+19delA		intron	N/A	ENSP00000359151.3	P11182
	DBT	ENST00000370131.3	TSL:1	c.251+19delA		intron	N/A	ENSP00000359150.3	Q5VVL7
	DBT	ENST00000681617.1		c.251+19delA		intron	N/A	ENSP00000505544.1	A0A7P0Z494

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 8.93e-7 AC: 1 AN: 1120194 Hom.: 0 Cov.: 16 AF XY: 0.00 AC XY: 0 AN XY: 572662

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

African (AFR) AF: 0.00 AC: 0 AN: 26730

American (AMR) AF: 0.00 AC: 0 AN: 43398

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23802

East Asian (EAS) AF: 0.00 AC: 0 AN: 37722

South Asian (SAS) AF: 0.00 AC: 0 AN: 74840

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52636

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4688

European-Non Finnish (NFE) AF: 0.00000124 AC: 1 AN: 807498

Other (OTH) AF: 0.00 AC: 0 AN: 48880

⚠️ 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 Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-4.1

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;