X-19344053-G-A

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_ModerateBP6BS1BS2

The NM_000284.4(PDHA1):c.16G>A(p.Ala6Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000215 in 1,206,890 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 9 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A6A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000071 ( 0 hom., 2 hem., cov: 25)

Exomes 𝑓: 0.000016 ( 0 hom. 7 hem. )

Consequence

PDHA1
NM_000284.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: 2.13

Variant links:

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]

PDHA1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -11 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.18768415).

BP6

Variant X-19344053-G-A is Benign according to our data. Variant chrX-19344053-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 803731.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}.

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000071 (8/112662) while in subpopulation AMR AF= 0.000649 (7/10784). AF 95% confidence interval is 0.000304. There are 0 homozygotes in gnomad4. There are 2 alleles in male gnomad4 subpopulation. Median coverage is 25. This position pass quality control queck.

BS2

High Hemizygotes in GnomAd at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PDHA1	NM_000284.4 linkuse as main transcript	c.16G>A	p.Ala6Thr	missense_variant	1/11	ENST00000422285.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PDHA1	ENST00000422285.7 linkuse as main transcript	c.16G>A	p.Ala6Thr	missense_variant	1/11	1	NM_000284.4	P1	P08559-1

Frequencies

GnomAD3 genomes

AF:

0.0000710

AC:

AN:

112609

Hom.:

Cov.:

AF XY:

0.0000575

AC XY:

AN XY:

34769

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000650

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000188

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000572

AC:

AN:

174739

Hom.:

AF XY:

0.0000158

AC XY:

AN XY:

63289

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000131

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000165

AC:

AN:

1094228

Hom.:

Cov.:

AF XY:

0.0000194

AC XY:

AN XY:

361298

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000569

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000178

Gnomad4 OTH exome

AF:

0.0000218

GnomAD4 genome

AF:

0.0000710

AC:

AN:

112662

Hom.:

Cov.:

AF XY:

0.0000574

AC XY:

AN XY:

34832

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000649

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000188

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000416

ExAC

AF:

0.0000331

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Pyruvate dehydrogenase E1-alpha deficiency

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Aug 16, 2022	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 6 of the PDHA1 protein (p.Ala6Thr). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with PDHA1-related conditions. ClinVar contains an entry for this variant (Variation ID: 803731). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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. -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 18, 2023

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Uncertain

0.083

BayesDel_noAF

Benign

-0.12

Cadd

Benign

Dann

Uncertain

1.0

FATHMM_MKL

Benign

0.70

LIST_S2

Benign

0.74

T;T;T;T;T;T;T;T

M_CAP

Pathogenic

0.73

MetaRNN

Benign

0.19

T;T;T;T;T;T;T;T

MetaSVM

Uncertain

0.50

MutationAssessor

Benign

0.84

L;L;L;.;.;L;.;.

MutationTaster

Benign

0.92

N;N;N;N;N

PrimateAI

Uncertain

0.68

PROVEAN

Benign

-0.32

N;N;N;N;N;N;N;N

REVEL

Uncertain

0.40

Sift

Benign

0.43

T;T;T;T;T;T;T;T

Sift4G

Benign

0.54

T;T;T;T;T;T;T;T

Polyphen

0.0060

.;.;.;.;.;B;.;.

Vest4

0.44

MutPred

0.29

Loss of helix (P = 0.0196);Loss of helix (P = 0.0196);Loss of helix (P = 0.0196);Loss of helix (P = 0.0196);Loss of helix (P = 0.0196);Loss of helix (P = 0.0196);Loss of helix (P = 0.0196);Loss of helix (P = 0.0196);

MVP

0.90

MPC

1.3

ClinPred

0.29

GERP RS

4.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.9

Varity_R

0.085

gMVP

0.37

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over