rs760851100

Positions:

• chr16-31111301-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP3

The NM_005881.4(BCKDK):​c.847G>A​(p.Ala283Thr) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000171 in 1,461,870 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000017 (0 hom.)
• Consequence: BCKDK NM_005881.4 missense, splice_region
• Scores: Splicing: ADA: 0.9913
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 7.26

Genes affected

BCKDK (HGNC:16902): (branched chain keto acid dehydrogenase kinase) The branched-chain alpha-ketoacid dehydrogenase complex (BCKD) is an important regulator of the valine, leucine, and isoleucine catabolic pathways. The protein encoded by this gene is found in the mitochondrion, where it phosphorylates and inactivates BCKD. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2012]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a domain Histidine kinase (size 245) in uniprot entity BCKD_HUMAN there are 6 pathogenic changes around while only 2 benign (75%) in NM_005881.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BCKDK	NM_005881.4	c.847G>A	p.Ala283Thr	missense_variant, splice_region_variant	10/12	ENST00000219794.11
BCKDK	NM_001122957.4	c.847G>A	p.Ala283Thr	missense_variant, splice_region_variant	10/11
BCKDK	XM_017022859.2	c.847G>A	p.Ala283Thr	missense_variant, splice_region_variant	10/12
BCKDK	NM_001271926.3	c.845+82G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BCKDK	ENST00000219794.11	c.847G>A	p.Ala283Thr	missense_variant, splice_region_variant	10/12	1	NM_005881.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251432 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135894

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000171 AC: 25 AN: 1461870 Hom.: 0 Cov.: 33 AF XY: 0.0000193 AC XY: 14 AN XY: 727236

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000225

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.000102 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Branched-chain keto acid dehydrogenase kinase deficiency Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 25, 2018	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -
Uncertain significance, criteria provided, single submitter	clinical testing	Undiagnosed Diseases Network, NIH	Mar 16, 2018	- -

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 09, 2016	The A283T variant in the BCKDK gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The A283T variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The A283T variant is a non-conservative amino acid substitution, which occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret A283T as a variant of uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 27, 2014	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.38
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.83	D;.;D
Eigen	Pathogenic	0.98
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Uncertain	0.21	D
MetaRNN	Pathogenic	0.88	D;D;D
MetaSVM	Uncertain	0.68	D
MutationAssessor	Pathogenic	4.1	H;H;H
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-3.9	D;D;D
REVEL	Pathogenic	0.83
Sift	Pathogenic	0.0	D;D;D
Sift4G	Uncertain	0.0040	D;D;D
Polyphen		0.99	D;.;D
Vest4		0.83
MutPred		0.56		Gain of glycosylation at A283 (P = 0.0828);Gain of glycosylation at A283 (P = 0.0828);Gain of glycosylation at A283 (P = 0.0828);
MVP		0.95
MPC		1.5
ClinPred		1.0	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.78
gMVP		0.84

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Pathogenic	0.90
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

Publications

LitVar

Other links and lift over

dbSNP: rs760851100; hg19: chr16-31122622;