chrX-19344084-C-T

Position:

• chrX-19344084-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_000284.4(PDHA1):​c.47C>T​(p.Ser16Phe) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 25)
• Consequence: PDHA1 NM_000284.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 3.61

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
• BP4: Computational evidence support a benign effect (MetaRNN=0.32869193).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PDHA1	NM_000284.4	c.47C>T	p.Ser16Phe	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.47C>T	p.Ser16Phe	missense_variant	1/11	1	NM_000284.4	ENSP00000394382	P1

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 25

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Pyruvate dehydrogenase E1-alpha deficiency Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 02, 2023

Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PDHA1 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant has not been reported in the literature in individuals affected with PDHA1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 16 of the PDHA1 protein (p.Ser16Phe). -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Dec 07, 2023

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
CADD	Benign	23
DANN	Benign	0.94
DEOGEN2	Benign	0.015	.;.;.;T;T;T;T;T
FATHMM_MKL	Benign	0.64	D
LIST_S2	Benign	0.47	T;T;T;T;T;T;T;T
M_CAP	Pathogenic	0.64	D
MetaRNN	Benign	0.33	T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.47	D
MutationAssessor	Benign	1.2	L;L;L;.;.;L;.;.
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-0.48	N;N;N;N;N;N;N;N
REVEL	Uncertain	0.36
Sift	Benign	0.58	T;T;D;D;D;T;T;T
Sift4G	Benign	0.11	T;T;T;T;D;T;T;T
Polyphen		0.043	.;.;.;.;.;B;.;.
Vest4		0.17
MutPred		0.35		Loss of disorder (P = 0.0024);Loss of disorder (P = 0.0024);Loss of disorder (P = 0.0024);Loss of disorder (P = 0.0024);Loss of disorder (P = 0.0024);Loss of disorder (P = 0.0024);Loss of disorder (P = 0.0024);Loss of disorder (P = 0.0024);
MVP		0.87
MPC		1.4
ClinPred		0.59	D
GERP RS		5.0
Varity_R		0.16
gMVP		0.40

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-19362202;