rs34442879

Variant names:

• chr19-41414125-C-T
• rs34442879
• NM_000709.4:c.452C>T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000709.4(BCKDHA):​c.452C>T​(p.Thr151Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00885 in 1,613,696 control chromosomes in the GnomAD database, including 98 homozygotes. In-silico tool predicts 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. T151T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0079 (14 hom., cov: 32)
  • Exomes 𝑓: 0.0090 (84 hom.)
• Consequence: BCKDHA NM_000709.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: 1.31
• Publications: 13 publications found

Genes affected

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

ENSG00000255730 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 6 uncertain in NM_000709.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.017781347).
• BP6: Variant 19-41414125-C-T is Benign according to our data. Variant chr19-41414125-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 93361.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 = 0.00786 (1198/152328) while in subpopulation NFE AF = 0.0103 (701/68038). AF 95% confidence interval is 0.00967. There are 14 homozygotes in GnomAd4. There are 647 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 14 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000709.4. 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.452C>T	p.Thr151Met	missense	Exon 4 of 9	NP_000700.1	P12694-1
	BCKDHA	NM_001164783.2		c.452C>T	p.Thr151Met	missense	Exon 4 of 9	NP_001158255.1	Q59EI3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BCKDHA	ENST00000269980.7	TSL:1 MANE Select	c.452C>T	p.Thr151Met	missense	Exon 4 of 9	ENSP00000269980.2	P12694-1
	ENSG00000255730	ENST00000540732.3	TSL:2	c.554C>T	p.Thr185Met	missense	Exon 5 of 10	ENSP00000443246.1	F5H5P2
	BCKDHA	ENST00000919033.1		c.452C>T	p.Thr151Met	missense	Exon 4 of 10	ENSP00000589092.1

Frequencies

GnomAD3 genomes AF: 0.00786 AC: 1197 AN: 152210 Hom.: 14 Cov.: 32

Gnomad AFR AF: 0.00150

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00510

Gnomad ASJ AF: 0.00403

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00414

Gnomad FIN AF: 0.0261

Gnomad MID AF: 0.0538

Gnomad NFE AF: 0.0103

Gnomad OTH AF: 0.0125

GnomAD2 exomes AF: 0.00976 AC: 2447 AN: 250702 AF XY: 0.0101

Gnomad AFR exome AF: 0.00142

Gnomad AMR exome AF: 0.00431

Gnomad ASJ exome AF: 0.00498

Gnomad EAS exome AF: 0.0000545

Gnomad FIN exome AF: 0.0259

Gnomad NFE exome AF: 0.0125

Gnomad OTH exome AF: 0.0141

GnomAD4 exome AF: 0.00895 AC: 13086 AN: 1461368 Hom.: 84 Cov.: 34 AF XY: 0.00892 AC XY: 6488 AN XY: 726988

African (AFR) AF: 0.00185 AC: 62 AN: 33480

American (AMR) AF: 0.00436 AC: 195 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00536 AC: 140 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00541 AC: 467 AN: 86258

European-Finnish (FIN) AF: 0.0251 AC: 1331 AN: 52932

Middle Eastern (MID) AF: 0.0468 AC: 270 AN: 5768

European-Non Finnish (NFE) AF: 0.00905 AC: 10061 AN: 1111984

Other (OTH) AF: 0.00926 AC: 559 AN: 60386

GnomAD4 genome AF: 0.00786 AC: 1198 AN: 152328 Hom.: 14 Cov.: 32 AF XY: 0.00869 AC XY: 647 AN XY: 74476

African (AFR) AF: 0.00149 AC: 62 AN: 41572

American (AMR) AF: 0.00510 AC: 78 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00403 AC: 14 AN: 3472

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5188

South Asian (SAS) AF: 0.00414 AC: 20 AN: 4830

European-Finnish (FIN) AF: 0.0261 AC: 277 AN: 10610

Middle Eastern (MID) AF: 0.0612 AC: 18 AN: 294

European-Non Finnish (NFE) AF: 0.0103 AC: 701 AN: 68038

Other (OTH) AF: 0.0123 AC: 26 AN: 2108

Alfa AF: 0.00943 Hom.: 35

Bravo AF: 0.00627

TwinsUK AF: 0.00944 AC: 35

ALSPAC AF: 0.00571 AC: 22

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.0106 AC: 91

ExAC AF: 0.0106 AC: 1290

Asia WGS AF: 0.00231 AC: 9 AN: 3478

EpiCase AF: 0.0109

EpiControl AF: 0.0120

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	4	Maple syrup urine disease (4)
-	-	4	not specified (4)
-	-	2	Maple syrup urine disease type 1A (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Uncertain	-0.060
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.53	D
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Benign	0.68	D
LIST_S2	Uncertain	0.93	D
MetaRNN	Benign	0.018	T
MetaSVM	Pathogenic	0.80	D
MutationAssessor	Benign	1.8	L
PhyloP100		1.3
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-1.2	N
REVEL	Uncertain	0.43
Sift	Uncertain	0.020	D
Sift4G	Uncertain	0.044	D
Polyphen		0.96	D
Vest4		0.18
MPC		1.2
ClinPred		0.023	T
GERP RS		4.7
Varity_R		0.15
gMVP		0.70
Mutation Taster		=57/43	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: rs34442879; hg19: chr19-41920030; COSMIC: COSV54197148; COSMIC: COSV54197148;