rs767503319

Variant names:

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6BP7BS1BS2

The NM_000284.4(PDHA1):c.984T>C(p.Asn328Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000833 in 1,177,023 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 28 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).

Frequency

Genomes: 𝑓 0.000090 ( 0 hom., 0 hem., cov: 23)

Exomes 𝑓: 0.000083 ( 0 hom. 28 hem. )

Consequence

PDHA1
NM_000284.4 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3

Conservation

PhyloP100: 0.186

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 -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.59).

BP6

Variant X-19359000-T-C is Benign according to our data. Variant chrX-19359000-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 211893.

BP7

Synonymous conserved (PhyloP=0.186 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0000896 (10/111586) while in subpopulation NFE AF = 0.000151 (8/53129). AF 95% confidence interval is 0.0000745. There are 0 homozygotes in GnomAd4. There are 0 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.

BS2

High Hemizygotes in GnomAdExome4 at 28 XL,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PDHA1	NM_000284.4 link	c.984T>C	p.Asn328Asn	synonymous_variant	Exon 10 of 11	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.984T>C	p.Asn328Asn	synonymous_variant	Exon 10 of 11	1	NM_000284.4	ENSP00000394382.2		P08559-1

Frequencies

GnomAD3 genomes

AF:

0.0000896

AC:

AN:

111586

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000326

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.000151

Gnomad OTH

AF:

0.000669

GnomAD2 exomes

AF:

0.0000327

AC:

AN:

183318

AF XY:

0.0000295

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000734

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000826

AC:

AN:

1065437

Hom.:

Cov.:

AF XY:

0.0000838

AC XY:

AN XY:

334097

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

25788

American (AMR)

AF:

0.00

AC:

AN:

35177

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19172

East Asian (EAS)

AF:

0.00

AC:

AN:

30101

South Asian (SAS)

AF:

0.00

AC:

AN:

53393

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40520

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4050

European-Non Finnish (NFE)

AF:

0.000103

AC:

AN:

812216

Other (OTH)

AF:

0.0000888

AC:

AN:

45020

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<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:

0.0000896

AC:

AN:

111586

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33750

show subpopulations

African (AFR)

AF:

0.0000326

AC:

AN:

30672

American (AMR)

AF:

0.00

AC:

AN:

10500

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2643

East Asian (EAS)

AF:

0.00

AC:

AN:

3548

South Asian (SAS)

AF:

0.00

AC:

AN:

2642

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6031

Middle Eastern (MID)

AF:

0.00

AC:

AN:

239

European-Non Finnish (NFE)

AF:

0.000151

AC:

AN:

53129

Other (OTH)

AF:

0.000669

AC:

AN:

1495

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000142

Hom.:

Bravo

AF:

0.0000529

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 23, 2014

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Pyruvate dehydrogenase E1-alpha deficiency

Benign:1

Feb 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Benign:1

Sep 06, 2017

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Pyruvate dehydrogenase complex deficiency

Benign:1

Oct 28, 2019

Natera, Inc.

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.59

CADD

Benign

5.6

(source)

DANN

Benign

0.87

PhyloP100

0.19

Mutation Taster

=100/0

polymorphism

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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