rs760851100

Variant names:

• chr16-31111301-G-A
• rs760851100
• NM_005881.4:c.847G>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. 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
• Publications: 2 publications found

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]

BCKDK Gene-Disease associations (from GenCC):

• branched-chain keto acid dehydrogenase kinase deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005881.4. 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
	BCKDK	NM_005881.4	MANE Select	c.847G>A	p.Ala283Thr	missense splice_region	Exon 10 of 12	NP_005872.2	O14874-1
	BCKDK	NM_001122957.4		c.847G>A	p.Ala283Thr	missense splice_region	Exon 10 of 11	NP_001116429.1	O14874-3
	BCKDK	NM_001271926.3		c.845+82G>A		intron	N/A	NP_001258855.1	O14874-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BCKDK	ENST00000219794.11	TSL:1 MANE Select	c.847G>A	p.Ala283Thr	missense splice_region	Exon 10 of 12	ENSP00000219794.6	O14874-1
	BCKDK	ENST00000287507.7	TSL:1	c.845+82G>A		intron	N/A	ENSP00000287507.3	O14874-2
	BCKDK	ENST00000394951.5	TSL:5	c.847G>A	p.Ala283Thr	missense splice_region	Exon 11 of 13	ENSP00000378405.1	O14874-1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000119 AC: 3 AN: 251432 AF XY: 0.0000147

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 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

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000225 AC: 25 AN: 1112000

Other (OTH) AF: 0.00 AC: 0 AN: 60394

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

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	Branched-chain keto acid dehydrogenase kinase deficiency (2)
-	2	-	not provided (2)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Pathogenic	0.98
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.21	D
MetaRNN	Pathogenic	0.88	D
MetaSVM	Uncertain	0.68	D
MutationAssessor	Pathogenic	4.1	H
PhyloP100		7.3
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-3.9	D
REVEL	Pathogenic	0.83
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0040	D
Polyphen		0.99	D
Vest4		0.83
MutPred		0.56		Gain of glycosylation at A283 (P = 0.0828)
MVP		0.95
MPC		1.5
ClinPred		1.0	D
GERP RS		5.8
PromoterAI		-0.010	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.78
gMVP		0.84
Mutation Taster		=37/63	disease causing

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

Other links and lift over

dbSNP: rs760851100; hg19: chr16-31122622;