rs12021720

Variant names:

• chr1-100206504-T-C
• rs12021720
• NM_001918.5:c.1150A>G

Your query was ambiguous. Multiple possible variants found:

• chr1-100206504-T-C
• chr1-100206504-T-A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001918.5(DBT):​c.1150A>G​(p.Ser384Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.908 in 1,613,388 control chromosomes in the GnomAD database, including 665,858 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. S384S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.88 (58729 hom., cov: 31)
  • Exomes 𝑓: 0.91 (607129 hom.)
• Consequence: DBT NM_001918.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 1.94
• Publications: 53 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.0305434E-6).
• BP6: Variant 1-100206504-T-C is Benign according to our data. Variant chr1-100206504-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 128885.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.944 is higher than 0.05.

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.1150A>G	p.Ser384Gly	missense	Exon 9 of 11	NP_001909.4	P11182
	DBT	NM_001399969.1		c.607A>G	p.Ser203Gly	missense	Exon 10 of 12	NP_001386898.1	A0A7P0T9W1
	DBT	NM_001399972.1		c.607A>G	p.Ser203Gly	missense	Exon 10 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.1150A>G	p.Ser384Gly	missense	Exon 9 of 11	ENSP00000359151.3	P11182
	DBT	ENST00000681617.1		c.1276A>G	p.Ser426Gly	missense	Exon 10 of 12	ENSP00000505544.1	A0A7P0Z494
	DBT	ENST00000875462.1		c.1150A>G	p.Ser384Gly	missense	Exon 9 of 12	ENSP00000545521.1

Frequencies

GnomAD3 genomes AF: 0.876 AC: 133222 AN: 152050 Hom.: 58703 Cov.: 31

Gnomad AFR AF: 0.765

Gnomad AMI AF: 0.852

Gnomad AMR AF: 0.917

Gnomad ASJ AF: 0.913

Gnomad EAS AF: 0.967

Gnomad SAS AF: 0.953

Gnomad FIN AF: 0.934

Gnomad MID AF: 0.908

Gnomad NFE AF: 0.911

Gnomad OTH AF: 0.890

GnomAD2 exomes AF: 0.917 AC: 230704 AN: 251468 AF XY: 0.920

Gnomad AFR exome AF: 0.763

Gnomad AMR exome AF: 0.955

Gnomad ASJ exome AF: 0.917

Gnomad EAS exome AF: 0.969

Gnomad FIN exome AF: 0.931

Gnomad NFE exome AF: 0.908

Gnomad OTH exome AF: 0.913

GnomAD4 exome AF: 0.911 AC: 1331229 AN: 1461220 Hom.: 607129 Cov.: 43 AF XY: 0.913 AC XY: 663563 AN XY: 726956

African (AFR) AF: 0.763 AC: 25540 AN: 33454

American (AMR) AF: 0.951 AC: 42554 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.915 AC: 23924 AN: 26134

East Asian (EAS) AF: 0.980 AC: 38906 AN: 39692

South Asian (SAS) AF: 0.952 AC: 82111 AN: 86250

European-Finnish (FIN) AF: 0.929 AC: 49602 AN: 53390

Middle Eastern (MID) AF: 0.892 AC: 5142 AN: 5764

European-Non Finnish (NFE) AF: 0.907 AC: 1008536 AN: 1111428

Other (OTH) AF: 0.909 AC: 54914 AN: 60384

GnomAD4 genome AF: 0.876 AC: 133297 AN: 152168 Hom.: 58729 Cov.: 31 AF XY: 0.880 AC XY: 65449 AN XY: 74400

African (AFR) AF: 0.765 AC: 31723 AN: 41474

American (AMR) AF: 0.917 AC: 14026 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.913 AC: 3166 AN: 3468

East Asian (EAS) AF: 0.967 AC: 5001 AN: 5174

South Asian (SAS) AF: 0.952 AC: 4585 AN: 4814

European-Finnish (FIN) AF: 0.934 AC: 9897 AN: 10600

Middle Eastern (MID) AF: 0.912 AC: 268 AN: 294

European-Non Finnish (NFE) AF: 0.911 AC: 61969 AN: 68022

Other (OTH) AF: 0.891 AC: 1885 AN: 2116

Alfa AF: 0.902 Hom.: 160482

Bravo AF: 0.869

TwinsUK AF: 0.906 AC: 3361

ALSPAC AF: 0.907 AC: 3495

ESP6500AA AF: 0.775 AC: 3414

ESP6500EA AF: 0.902 AC: 7761

ExAC AF: 0.914 AC: 110942

Asia WGS AF: 0.926 AC: 3223 AN: 3478

EpiCase AF: 0.905

EpiControl AF: 0.904

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	3	Maple syrup urine disease (3)
-	-	2	not provided (2)
-	-	1	Maple syrup urine disease type 1A (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.044
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	14
DANN	Benign	0.15
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.59
FATHMM_MKL	Benign	0.017	N
MetaRNN	Benign	0.0000010	T
MetaSVM	Benign	-1.0	T
PhyloP100		1.9
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	3.0	N
REVEL	Benign	0.12
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Vest4		0.042
MPC		0.29
ClinPred		0.00015	T
GERP RS		4.4
gMVP		0.68
Mutation Taster		=100/0	polymorphism (auto)

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: rs12021720; hg19: chr1-100672060; COSMIC: COSV107457573; COSMIC: COSV107457573;