rs145749914

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000284.4(PDHA1):c.57+2482G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00418 in 867,742 control chromosomes in the GnomAD database, including 97 homozygotes. There are 916 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.019 ( 61 hom., 584 hem., cov: 23)

Exomes 𝑓: 0.0019 ( 36 hom. 332 hem. )

Consequence

PDHA1
NM_000284.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.568

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

Leigh syndrome
Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
pyruvate dehydrogenase E1-alpha deficiency
Inheritance: XL, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet, Ambry Genetics
Leigh syndrome with leukodystrophy
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

PDHA1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0022673607).

BP6

Variant X-19346576-G-A is Benign according to our data. Variant chrX-19346576-G-A is described in ClinVar as Benign. ClinVar VariationId is 377151.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0636 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PDHA1	NM_000284.4 link	c.57+2482G>A		intron_variant	Intron 1 of 10	ENST00000422285.7	NP_000275.1	P08559-1A0A024RBX9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PDHA1	ENST00000422285.7 link	c.57+2482G>A		intron_variant	Intron 1 of 10	1	NM_000284.4	ENSP00000394382.2		P08559-1

Frequencies

GnomAD3 genomes

AF:

0.0193

AC:

2161

AN:

111771

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0661

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00864

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00195

Gnomad SAS

AF:

0.000736

Gnomad FIN

AF:

0.000165

Gnomad MID

AF:

0.00418

Gnomad NFE

AF:

0.000320

Gnomad OTH

AF:

0.0125

GnomAD2 exomes

AF:

0.00205

AC:

106

AN:

51768

AF XY:

0.000314

show subpopulations

Gnomad AFR exome

AF:

0.0487

Gnomad AMR exome

AF:

0.00244

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00255

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000232

Gnomad OTH exome

AF:

0.00308

GnomAD4 exome

AF:

0.00194

AC:

1466

AN:

755919

Hom.:

Cov.:

AF XY:

0.00177

AC XY:

332

AN XY:

187189

show subpopulations

African (AFR)

AF:

0.0611

AC:

1033

AN:

16893

American (AMR)

AF:

0.00429

AC:

AN:

20534

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

14121

East Asian (EAS)

AF:

0.00229

AC:

AN:

22315

South Asian (SAS)

AF:

0.00

AC:

AN:

25599

European-Finnish (FIN)

AF:

0.00

AC:

AN:

21845

Middle Eastern (MID)

AF:

0.000604

AC:

AN:

3310

European-Non Finnish (NFE)

AF:

0.000175

AC:

105

AN:

598326

Other (OTH)

AF:

0.00567

AC:

187

AN:

32976

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

100

151

201

251

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

114

152

190

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0194

AC:

2164

AN:

111823

Hom.:

Cov.:

AF XY:

0.0171

AC XY:

584

AN XY:

34057

show subpopulations

African (AFR)

AF:

0.0660

AC:

2026

AN:

30693

American (AMR)

AF:

0.00863

AC:

AN:

10544

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2639

East Asian (EAS)

AF:

0.00195

AC:

AN:

3584

South Asian (SAS)

AF:

0.000738

AC:

AN:

2709

European-Finnish (FIN)

AF:

0.000165

AC:

AN:

6050

Middle Eastern (MID)

AF:

0.00459

AC:

AN:

218

European-Non Finnish (NFE)

AF:

0.000320

AC:

AN:

53167

Other (OTH)

AF:

0.0124

AC:

AN:

1534

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

144

215

287

359

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

110

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00747

Hom.:

Bravo

AF:

0.0218

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.00292

AC:

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jan 05, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Jun 09, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.082

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.33

CADD

Benign

1.7

(source)

DANN

Benign

0.81

DEOGEN2

Benign

0.0072

.;T

FATHMM_MKL

Benign

0.019

LIST_S2

Benign

0.42

T;T

MetaRNN

Benign

0.0023

T;T

MetaSVM

Uncertain

0.28

PhyloP100

-0.57

PrimateAI

Benign

0.43

PROVEAN

Benign

0.43

N;N

REVEL

Benign

0.24

Sift

Benign

0.10

T;T

Sift4G

Benign

0.30

T;T

Vest4

0.10

MVP

0.52

MPC

1.3

ClinPred

0.0078

GERP RS

0.43

gMVP

0.26

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over