1-100214929-A-G

Variant names:

• chr1-100214929-A-G
• rs121964999
• NM_001918.5:c.827T>C

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2 PM5 PP3_Strong

The NM_001918.5(DBT):​c.827T>C​(p.Phe276Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,900 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F276C) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: DBT NM_001918.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.95
• 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: Likely_pathogenic. The variant received 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-100214929-A-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 11943.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.941

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.827T>C	p.Phe276Ser	missense	Exon 7 of 11	NP_001909.4	P11182
	DBT	NM_001399969.1		c.284T>C	p.Phe95Ser	missense	Exon 8 of 12	NP_001386898.1	A0A7P0T9W1
	DBT	NM_001399972.1		c.284T>C	p.Phe95Ser	missense	Exon 8 of 12	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.827T>C	p.Phe276Ser	missense	Exon 7 of 11	ENSP00000359151.3	P11182
	DBT	ENST00000370131.3	TSL:1	c.827T>C	p.Phe276Ser	missense	Exon 7 of 8	ENSP00000359150.3	Q5VVL7
	DBT	ENST00000681617.1		c.827T>C	p.Phe276Ser	missense	Exon 7 of 12	ENSP00000505544.1	A0A7P0Z494

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460900 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726868

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.00 AC: 0 AN: 86242

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111104

Other (OTH) AF: 0.00 AC: 0 AN: 60364

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
CADD	Pathogenic	30
DANN	Uncertain	1.0
Eigen	Pathogenic	0.98
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Uncertain	0.040	D
PhyloP100		8.9
PrimateAI	Uncertain	0.69	T
PROVEAN	Pathogenic	-7.5	D
REVEL	Pathogenic	0.78
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Vest4		0.87
MutPred		0.81		Gain of glycosylation at F276 (P = 0.0155)
MVP		0.86
MPC		1.0
ClinPred		1.0	D
GERP RS		5.4
gMVP		0.87
Mutation Taster		=8/92	disease causing

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: rs121964999; hg19: chr1-100680485;