rs45500792

Variant names:

• chr19-41397794-T-G
• rs45500792
• ENST00000540732.3:c.211-12843T>G

Your query was ambiguous. Multiple possible variants found:

• chr19-41397794-T-G
• chr19-41397794-T-C

Variant summary

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

The ENST00000540732.3(ENSG00000255730):​c.211-12843T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.133 in 1,605,510 control chromosomes in the GnomAD database, including 15,174 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.10 (907 hom., cov: 33)
  • Exomes 𝑓: 0.14 (14267 hom.)
• Consequence: ENSG00000255730 ENST00000540732.3 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.433
• Publications: 25 publications found

Genes affected

ENSG00000255730 (HGNC:):

BCKDHA (HGNC:986): (branched chain keto acid dehydrogenase E1 subunit alpha) The branched-chain alpha-keto acid (BCAA) dehydrogenase (BCKD) complex is an innter mitochondrial enzyme complex that catalyzes the second major step in the catabolism of the branched-chain amino acids leucine, isoleucine, and valine. The BCKD complex consists of three catalytic components: a heterotetrameric (alpha2-beta2) branched-chain alpha-keto acid decarboxylase (E1), a dihydrolipoyl transacylase (E2), and a dihydrolipoamide dehydrogenase (E3). This gene encodes the alpha subunit of the decarboxylase (E1) component. Mutations in this gene result in maple syrup urine disease, type IA. Multiple transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Sep 2009]

BCKDHA Gene-Disease associations (from GenCC):

• maple syrup urine disease

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• maple syrup urine disease type 1A

  Inheritance: AR Classification: DEFINITIVE Submitted by: G2P, ClinGen, 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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BP6: Variant 19-41397794-T-G is Benign according to our data. Variant chr19-41397794-T-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 93334.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.148 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000540732.3. 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
	BCKDHA	NM_000709.4	MANE Select	c.-34T>G		upstream_gene	N/A	NP_000700.1	P12694-1
	BCKDHA	NM_001164783.2		c.-34T>G		upstream_gene	N/A	NP_001158255.1	Q59EI3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ENSG00000255730	ENST00000540732.3	TSL:2	c.211-12843T>G		intron	N/A	ENSP00000443246.1	F5H5P2
	BCKDHA	ENST00000906421.1		c.-34T>G		5_prime_UTR	Exon 1 of 9	ENSP00000576480.1
	ENSG00000255730	ENST00000604424.1	TSL:4	n.351-12843T>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.102 AC: 15471 AN: 152214 Hom.: 908 Cov.: 33

Gnomad AFR AF: 0.0382

Gnomad AMI AF: 0.156

Gnomad AMR AF: 0.106

Gnomad ASJ AF: 0.142

Gnomad EAS AF: 0.0468

Gnomad SAS AF: 0.157

Gnomad FIN AF: 0.0937

Gnomad MID AF: 0.127

Gnomad NFE AF: 0.138

Gnomad OTH AF: 0.100

GnomAD2 exomes AF: 0.115 AC: 28721 AN: 249866 AF XY: 0.121

Gnomad AFR exome AF: 0.0366

Gnomad AMR exome AF: 0.0674

Gnomad ASJ exome AF: 0.136

Gnomad EAS exome AF: 0.0528

Gnomad FIN exome AF: 0.0966

Gnomad NFE exome AF: 0.139

Gnomad OTH exome AF: 0.124

GnomAD4 exome AF: 0.136 AC: 197327 AN: 1453178 Hom.: 14267 Cov.: 30 AF XY: 0.137 AC XY: 99142 AN XY: 723392

African (AFR) AF: 0.0365 AC: 1215 AN: 33300

American (AMR) AF: 0.0713 AC: 3184 AN: 44678

Ashkenazi Jewish (ASJ) AF: 0.133 AC: 3473 AN: 26076

East Asian (EAS) AF: 0.0498 AC: 1976 AN: 39652

South Asian (SAS) AF: 0.158 AC: 13583 AN: 86032

European-Finnish (FIN) AF: 0.0973 AC: 5193 AN: 53390

Middle Eastern (MID) AF: 0.163 AC: 902 AN: 5528

European-Non Finnish (NFE) AF: 0.145 AC: 159816 AN: 1104462

Other (OTH) AF: 0.133 AC: 7985 AN: 60060

GnomAD4 genome AF: 0.102 AC: 15470 AN: 152332 Hom.: 907 Cov.: 33 AF XY: 0.100 AC XY: 7455 AN XY: 74484

African (AFR) AF: 0.0382 AC: 1590 AN: 41588

American (AMR) AF: 0.106 AC: 1621 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.142 AC: 493 AN: 3472

East Asian (EAS) AF: 0.0463 AC: 240 AN: 5178

South Asian (SAS) AF: 0.157 AC: 760 AN: 4832

European-Finnish (FIN) AF: 0.0937 AC: 995 AN: 10622

Middle Eastern (MID) AF: 0.122 AC: 36 AN: 294

European-Non Finnish (NFE) AF: 0.138 AC: 9380 AN: 68020

Other (OTH) AF: 0.101 AC: 213 AN: 2114

Alfa AF: 0.121 Hom.: 1412

Bravo AF: 0.0983

Asia WGS AF: 0.100 AC: 346 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Maple syrup urine disease (2)
-	-	1	BCKDHA-related disorder (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.93
DANN	Benign	0.50
PhyloP100		-0.43
PromoterAI		-0.13	Neutral
Mutation Taster		=300/0	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: rs45500792; hg19: chr19-41903699;