rs869312124

Variant names:

• chr19-41422361-G-C
• rs869312124
• NM_000709.4:c.844G>C

Your query was ambiguous. Multiple possible variants found:

• chr19-41422361-G-C
• chr19-41422361-G-A

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Moderate PP5_Moderate

The NM_000709.4(BCKDHA):​c.844G>C​(p.Asp282His) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,858 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: BCKDHA NM_000709.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 6.83
• Publications: 1 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: Likely_pathogenic. The variant received 8 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_000709.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.916
• PP5: Variant 19-41422361-G-C is Pathogenic according to our data. Variant chr19-41422361-G-C is described in ClinVar as Pathogenic. ClinVar VariationId is 204377.Status of the report is criteria_provided_single_submitter, 1 stars.

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.844G>C	p.Asp282His	missense	Exon 6 of 9	NP_000700.1	P12694-1
	BCKDHA	NM_001164783.2		c.844G>C	p.Asp282His	missense	Exon 6 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.844G>C	p.Asp282His	missense	Exon 6 of 9	ENSP00000269980.2	P12694-1
	ENSG00000255730	ENST00000540732.3	TSL:2	c.946G>C	p.Asp316His	missense	Exon 7 of 10	ENSP00000443246.1	F5H5P2
	BCKDHA	ENST00000919033.1		c.1072G>C	p.Asp358His	missense	Exon 7 of 10	ENSP00000589092.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461858 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727226

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

American (AMR) AF: 0.00 AC: 0 AN: 44722

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

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

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111994

Other (OTH) AF: 0.00 AC: 0 AN: 60390

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Maple syrup urine disease (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.75	D
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.87	D
M_CAP	Pathogenic	0.66	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.2	M
PhyloP100		6.8
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-7.0	D
REVEL	Pathogenic	0.88
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.95
MutPred		0.45		Gain of methylation at R314 (P = 0.0637)
MVP		0.97
MPC		2.1
ClinPred		1.0	D
GERP RS		4.9
Varity_R		0.95
gMVP		0.89
Mutation Taster		=3/97	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs869312124; hg19: chr19-41928266;