rs72973763

Variant names:

• chr1-100216040-T-C
• rs72973763
• NM_001918.5:c.715A>G
• DBT p.Ile239Val

Your query was ambiguous. Multiple possible variants found:

• chr1-100216040-T-C
• chr1-100216040-T-G
• chr1-100216040-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.715A>G​(p.Ile239Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00595 in 1,613,626 control chromosomes in the GnomAD database, including 535 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I239L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.032 (283 hom., cov: 32)
  • Exomes 𝑓: 0.0033 (252 hom.)
• Consequence: DBT NM_001918.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.0790
• Publications: 4 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=0.0017527044).
• BP6: Variant 1-100216040-T-C is Benign according to our data. Variant chr1-100216040-T-C is described in ClinVar as Benign. ClinVar VariationId is 94010.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.109 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.715A>G	p.Ile239Val	missense	Exon 6 of 11	NP_001909.4	P11182
	DBT	NM_001399969.1		c.172A>G	p.Ile58Val	missense	Exon 7 of 12	NP_001386898.1	A0A7P0T9W1
	DBT	NM_001399972.1		c.172A>G	p.Ile58Val	missense	Exon 7 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.715A>G	p.Ile239Val	missense	Exon 6 of 11	ENSP00000359151.3	P11182
	DBT	ENST00000370131.3	TSL:1	c.715A>G	p.Ile239Val	missense	Exon 6 of 8	ENSP00000359150.3	Q5VVL7
	DBT	ENST00000681617.1		c.715A>G	p.Ile239Val	missense	Exon 6 of 12	ENSP00000505544.1	A0A7P0Z494

Frequencies

GnomAD3 genomes AF: 0.0316 AC: 4804 AN: 152096 Hom.: 284 Cov.: 32

Gnomad AFR AF: 0.111

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00838

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.0239

GnomAD2 exomes AF: 0.00833 AC: 2094 AN: 251468 AF XY: 0.00611

Gnomad AFR exome AF: 0.116

Gnomad AMR exome AF: 0.00434

Gnomad ASJ exome AF: 0.00149

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000167

Gnomad OTH exome AF: 0.00342

GnomAD4 exome AF: 0.00327 AC: 4780 AN: 1461412 Hom.: 252 Cov.: 30 AF XY: 0.00283 AC XY: 2056 AN XY: 727060

African (AFR) AF: 0.116 AC: 3883 AN: 33462

American (AMR) AF: 0.00479 AC: 214 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00149 AC: 39 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39676

South Asian (SAS) AF: 0.000243 AC: 21 AN: 86250

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

Middle Eastern (MID) AF: 0.00347 AC: 20 AN: 5762

European-Non Finnish (NFE) AF: 0.000143 AC: 159 AN: 1111626

Other (OTH) AF: 0.00736 AC: 444 AN: 60366

GnomAD4 genome AF: 0.0316 AC: 4816 AN: 152214 Hom.: 283 Cov.: 32 AF XY: 0.0307 AC XY: 2286 AN XY: 74428

African (AFR) AF: 0.111 AC: 4623 AN: 41494

American (AMR) AF: 0.00837 AC: 128 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.000577 AC: 2 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000176 AC: 12 AN: 68014

Other (OTH) AF: 0.0237 AC: 50 AN: 2114

Alfa AF: 0.00679 Hom.: 93

Bravo AF: 0.0368

Asia WGS AF: 0.0110 AC: 38 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.000237

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.055
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	0.43
DANN	Benign	0.58
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.086	N
LIST_S2	Benign	0.56	T
MetaRNN	Benign	0.0018	T
MetaSVM	Benign	-0.96	T
PhyloP100		-0.079
PrimateAI	Benign	0.23	T
PROVEAN	Benign	0.16	N
REVEL	Benign	0.029
Sift	Benign	1.0	T
Sift4G	Benign	0.58	T
gMVP		0.25
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs72973763;

hg19: chr1-100681596;

COSMIC: COSV64495090;

COSMIC: COSV64495090;