X-19344066-G-C

Position:

• chrX-19344066-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_000284.4(PDHA1):​c.29G>C​(p.Arg10Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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 Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 24)
• Consequence: PDHA1 NM_000284.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 2.92

Genes affected

PDHA1 (HGNC:8806): (pyruvate dehydrogenase E1 subunit alpha 1) The pyruvate dehydrogenase (PDH) complex is a nuclear-encoded mitochondrial multienzyme complex that catalyzes the overall conversion of pyruvate to acetyl-CoA and CO(2), and provides the primary link between glycolysis and the tricarboxylic acid (TCA) cycle. The PDH complex is composed of multiple copies of three enzymatic components: pyruvate dehydrogenase (E1), dihydrolipoamide acetyltransferase (E2) and lipoamide dehydrogenase (E3). The E1 enzyme is a heterotetramer of two alpha and two beta subunits. This gene encodes the E1 alpha 1 subunit containing the E1 active site, and plays a key role in the function of the PDH complex. Mutations in this gene are associated with pyruvate dehydrogenase E1-alpha deficiency and X-linked Leigh syndrome. Alternatively spliced transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Mar 2010]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.973
• PP5: Variant X-19344066-G-C is Pathogenic according to our data. Variant chrX-19344066-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 10887.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PDHA1	NM_000284.4	c.29G>C	p.Arg10Pro	missense_variant	1/11	ENST00000422285.7	NP_000275.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PDHA1	ENST00000422285.7	c.29G>C	p.Arg10Pro	missense_variant	1/11	1	NM_000284.4	ENSP00000394382	P1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 24

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Pyruvate dehydrogenase E1-alpha deficiency Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 01, 1995

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.66
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.016	.;.;.;T;T;T;T;T
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.80	T;T;T;T;T;T;T;T
M_CAP	Pathogenic	0.96	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.6	M;M;M;.;.;M;.;.
MutationTaster	Benign	0.76	A;A;A;A;A
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-2.0	N;N;N;N;N;N;N;N
REVEL	Pathogenic	0.73
Sift	Benign	0.13	T;T;T;D;D;T;D;D
Sift4G	Uncertain	0.032	D;D;D;D;T;D;D;D
Polyphen		0.44	.;.;.;.;.;B;.;.
Vest4		0.61
MutPred		0.84		Loss of MoRF binding (P = 0.0036);Loss of MoRF binding (P = 0.0036);Loss of MoRF binding (P = 0.0036);Loss of MoRF binding (P = 0.0036);Loss of MoRF binding (P = 0.0036);Loss of MoRF binding (P = 0.0036);Loss of MoRF binding (P = 0.0036);Loss of MoRF binding (P = 0.0036);
MVP		1.0
MPC		2.6
ClinPred		0.96	D
GERP RS		3.1
Varity_R		0.67
gMVP		0.54

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

LitVar

Other links and lift over

dbSNP: rs137853257; hg19: chrX-19362184;