rs146249007

Variant names:

• chr1-100216031-A-G
• rs146249007
• NM_001918.5:c.724T>C

Your query was ambiguous. Multiple possible variants found:

• chr1-100216031-A-G
• chr1-100216031-A-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001918.5(DBT):​c.724T>C​(p.Ser242Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00947 in 1,613,176 control chromosomes in the GnomAD database, including 90 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0084 (11 hom., cov: 32)
  • Exomes 𝑓: 0.0096 (79 hom.)
• Consequence: DBT NM_001918.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 0.899
• Publications: 8 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=0.0040974617).
• BP6: Variant 1-100216031-A-G is Benign according to our data. Variant chr1-100216031-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 94011.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00841 (1280/152134) while in subpopulation NFE AF = 0.0134 (908/68000). AF 95% confidence interval is 0.0126. There are 11 homozygotes in GnomAd4. There are 599 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DBT	NM_001918.5	MANE Select	c.724T>C	p.Ser242Pro	missense	Exon 6 of 11	NP_001909.4	P11182
	DBT	NM_001399969.1		c.181T>C	p.Ser61Pro	missense	Exon 7 of 12	NP_001386898.1	A0A7P0T9W1
	DBT	NM_001399972.1		c.181T>C	p.Ser61Pro	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.724T>C	p.Ser242Pro	missense	Exon 6 of 11	ENSP00000359151.3	P11182
	DBT	ENST00000370131.3	TSL:1	c.724T>C	p.Ser242Pro	missense	Exon 6 of 8	ENSP00000359150.3	Q5VVL7
	DBT	ENST00000681617.1		c.724T>C	p.Ser242Pro	missense	Exon 6 of 12	ENSP00000505544.1	A0A7P0Z494

Frequencies

GnomAD3 genomes AF: 0.00843 AC: 1281 AN: 152016 Hom.: 11 Cov.: 32

Gnomad AFR AF: 0.00184

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0100

Gnomad ASJ AF: 0.00749

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.00795

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0134

Gnomad OTH AF: 0.0100

GnomAD2 exomes AF: 0.00855 AC: 2151 AN: 251452 AF XY: 0.00872

Gnomad AFR exome AF: 0.00135

Gnomad AMR exome AF: 0.00471

Gnomad ASJ exome AF: 0.00754

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00818

Gnomad NFE exome AF: 0.0138

Gnomad OTH exome AF: 0.0109

GnomAD4 exome AF: 0.00958 AC: 13993 AN: 1461042 Hom.: 79 Cov.: 30 AF XY: 0.00965 AC XY: 7018 AN XY: 726934

African (AFR) AF: 0.00131 AC: 44 AN: 33466

American (AMR) AF: 0.00508 AC: 227 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00781 AC: 204 AN: 26128

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39678

South Asian (SAS) AF: 0.00301 AC: 260 AN: 86248

European-Finnish (FIN) AF: 0.00891 AC: 476 AN: 53416

Middle Eastern (MID) AF: 0.00868 AC: 50 AN: 5760

European-Non Finnish (NFE) AF: 0.0110 AC: 12206 AN: 1111256

Other (OTH) AF: 0.00868 AC: 524 AN: 60366

GnomAD4 genome AF: 0.00841 AC: 1280 AN: 152134 Hom.: 11 Cov.: 32 AF XY: 0.00806 AC XY: 599 AN XY: 74348

African (AFR) AF: 0.00183 AC: 76 AN: 41508

American (AMR) AF: 0.0100 AC: 153 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00749 AC: 26 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00228 AC: 11 AN: 4824

European-Finnish (FIN) AF: 0.00795 AC: 84 AN: 10564

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

European-Non Finnish (NFE) AF: 0.0134 AC: 908 AN: 68000

Other (OTH) AF: 0.00993 AC: 21 AN: 2114

Alfa AF: 0.0108 Hom.: 38

Bravo AF: 0.00740

TwinsUK AF: 0.00836 AC: 31

ALSPAC AF: 0.0127 AC: 49

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.0103 AC: 89

ExAC AF: 0.00959 AC: 1165

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.0118

EpiControl AF: 0.0117

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	Maple syrup urine disease (5)
-	-	4	not specified (4)
-	-	3	not provided (3)
-	-	1	Maple syrup urine disease type 1A (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	9.6
DANN	Benign	0.84
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.99
FATHMM_MKL	Benign	0.35	N
LIST_S2	Benign	0.60	T
MetaRNN	Benign	0.0041	T
MetaSVM	Benign	-0.95	T
PhyloP100		0.90
PrimateAI	Benign	0.36	T
PROVEAN	Benign	0.0	N
REVEL	Benign	0.026
Sift	Benign	0.33	T
Sift4G	Benign	0.26	T
Vest4		0.25
MVP		0.18
MPC		0.53
ClinPred		0.00031	T
GERP RS		0.24
gMVP		0.54
Mutation Taster		=97/3	polymorphism

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: rs146249007; hg19: chr1-100681587; COSMIC: COSV106109030; COSMIC: COSV106109030;