19-41424582-T-C

Position:

• chr19-41424582-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PM5 PP3_Moderate PP5

The NM_000709.4(BCKDHA):​c.1312T>C​(p.Tyr438His) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y438N) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BCKDHA NM_000709.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 5.59

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]

ENSG00000255730 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-41424582-T-A is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.912
• PP5: Variant 19-41424582-T-C is Pathogenic according to our data. Variant chr19-41424582-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1344509.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BCKDHA	NM_000709.4	c.1312T>C	p.Tyr438His	missense_variant	9/9	ENST00000269980.7	NP_000700.1
BCKDHA	NM_001164783.2	c.1309T>C	p.Tyr437His	missense_variant	9/9		NP_001158255.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BCKDHA	ENST00000269980.7	c.1312T>C	p.Tyr438His	missense_variant	9/9	1	NM_000709.4	ENSP00000269980.2
ENSG00000255730	ENST00000540732.3	c.1414T>C	p.Tyr472His	missense_variant	10/10	2		ENSP00000443246.1
BCKDHA	ENST00000457836.6	c.1321T>C	p.Tyr441His	missense_variant	9/9	2		ENSP00000416000.2
BCKDHA	ENST00000544905.1	c.141T>C	p.Thr47Thr	synonymous_variant	2/2	2		ENSP00000445727.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Maple syrup urine disease Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Suma Genomics	-	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	-	- -

Maple syrup urine disease type 1A Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Neuberg Centre For Genomic Medicine, NCGM

-

he missense variant c.1312T>C (p.Tyr438His) in the BCKDHA gene has been reported previously in a homozygous state in a female infant affected with Maple syrup urine disease (MSUD). The p.Y438H mutation appears to preclude the Hbond interaction of Y438 and is expected to destabilize the structure assembly. The BCKDHA Y438 residue is one of the most frequently affected residue in MSUD patients (Bashyam et al., 2012). A different pathogenic missense variant p.Tyr438Asn has been reported at the same position in patients affected with MSUD (Strauss KA, et al., 2006). This variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. It is submitted to ClinVar as Likely Pathogenic. The amino acid Tyrosine at position 438 is changed to a Histidine changing protein sequence and it might alter its composition and physico-chemical properties. Multiple lines of computational evidence (Polyphen-Damaging, SIFT-Damaging and MutationTaster - Disease causing) predict a damaging effect on protein structure and function for this variant. The amino acid change p.Tyr438His in BCKDHA is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. The same variant has been observed in heterozygous state in spouse [NCGM ID-30207400395] and in homozygous state in affected child. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.33	.;T;.
Eigen	Pathogenic	0.71
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.93	D;D;D
M_CAP	Pathogenic	0.87	D
MetaRNN	Pathogenic	0.91	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.3	.;M;.
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-4.7	D;D;D
REVEL	Pathogenic	0.95
Sift	Uncertain	0.0010	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	.;D;.
Vest4		0.81
MutPred		0.71		Gain of disorder (P = 0.0126);.;.;
MVP		0.96
MPC		0.43
ClinPred		1.0	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.91
gMVP		0.93

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-41930487;