X-19357664-A-T

Variant names:

• chrX-19357664-A-T
• NM_000284.4:c.844A>T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP3 BP6_Moderate

The NM_000284.4(PDHA1):​c.844A>T​(p.Met282Leu) variant causes a missense change involving the alteration of a 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 Likely benign (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: PDHA1 NM_000284.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 8.92

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.758
• BP6: Variant X-19357664-A-T is Benign according to our data. Variant chrX-19357664-A-T is described in ClinVar as [Likely_benign]. Clinvar id is 2801658.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PDHA1	NM_000284.4	c.844A>T	p.Met282Leu	missense_variant	Exon 9 of 11	ENST00000422285.7	NP_000275.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PDHA1	ENST00000422285.7	c.844A>T	p.Met282Leu	missense_variant	Exon 9 of 11	1	NM_000284.4	ENSP00000394382.2

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 23

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Pyruvate dehydrogenase E1-alpha deficiency Benign:1

Jul 21, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Benign	22
DANN	Benign	0.92
DEOGEN2	Uncertain	0.54	.;.;.;D;T
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.75	T;T;T;T;D
M_CAP	Pathogenic	0.70	D
MetaRNN	Uncertain	0.63	D;D;D;D;D
MetaSVM	Uncertain	-0.080	T
MutationAssessor	Benign	-1.0	.;.;.;N;.
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-0.69	N;N;N;N;N
REVEL	Uncertain	0.59
Sift	Benign	0.74	T;T;T;T;T
Sift4G	Benign	1.0	T;T;T;T;T
Polyphen		0.0020	.;.;.;B;.
Vest4		0.58
MutPred		0.81		.;.;.;Loss of methylation at K277 (P = 0.052);.;
MVP		0.99
MPC		1.2
ClinPred		0.90	D
GERP RS		5.5
Varity_R		0.58
gMVP		0.92

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: chrX-19375782;