rs762505127

Variant names:

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 2P and 9B. PM4BP6BS1BS2

The NM_000284.4(PDHA1):c.1173_*5delAGGGGA(p.Ter391delins???) variant causes a stop lost, conservative inframe deletion change. The variant allele was found at a frequency of 0.0000655 in 1,205,774 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 22 hemizygotes in GnomAD. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000063 ( 0 hom., 2 hem., cov: 22)

Exomes 𝑓: 0.000066 ( 0 hom. 20 hem. )

Consequence

PDHA1
NM_000284.4 stop_lost, conservative_inframe_deletion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5

Conservation

PhyloP100: 7.16

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 -7 ACMG points.

PM4

Stoplost variant in NM_000284.4 Downstream stopcodon found after 427 codons.

BP6

Variant X-19359651-TAAGGGG-T is Benign according to our data. Variant chrX-19359651-TAAGGGG-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 421578.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000063 (7/111140) while in subpopulation NFE AF = 0.000113 (6/53037). AF 95% confidence interval is 0.0000485. There are 0 homozygotes in GnomAd4. There are 2 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.

BS2

High Hemizygotes in GnomAd4 at 2 XL,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PDHA1	NM_000284.4 link	c.1173_*5delAGGGGA	p.Ter391delins???	stop_lost, conservative_inframe_deletion	Exon 11 of 11	ENST00000422285.7	NP_000275.1	P08559-1A0A024RBX9
PDHA1	NM_000284.4 link	c.1173_*5delAGGGGA		3_prime_UTR_variant	Exon 11 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.1173_*5delAGGGGA	p.Ter391delins???	stop_lost, conservative_inframe_deletion	Exon 11 of 11	1	NM_000284.4	ENSP00000394382.2		P08559-1
PDHA1	ENST00000422285.7 link	c.1173_*5delAGGGGA		3_prime_UTR_variant	Exon 11 of 11	1	NM_000284.4	ENSP00000394382.2		P08559-1

Frequencies

GnomAD3 genomes

AF:

0.0000630

AC:

AN:

111140

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000966

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:

0.000113

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000654

AC:

AN:

183377

AF XY:

0.000118

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000365

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000134

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000658

AC:

AN:

1094634

Hom.:

AF XY:

0.0000555

AC XY:

AN XY:

360062

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26320

American (AMR)

AF:

0.00

AC:

AN:

35202

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19365

East Asian (EAS)

AF:

0.00

AC:

AN:

30194

South Asian (SAS)

AF:

0.00

AC:

AN:

54055

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40490

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4123

European-Non Finnish (NFE)

AF:

0.0000858

AC:

AN:

838894

Other (OTH)

AF:

0.00

AC:

AN:

45991

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.459

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:

0.0000630

AC:

AN:

111140

Hom.:

Cov.:

AF XY:

0.0000600

AC XY:

AN XY:

33356

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30554

American (AMR)

AF:

0.0000966

AC:

AN:

10357

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2642

East Asian (EAS)

AF:

0.00

AC:

AN:

3540

South Asian (SAS)

AF:

0.00

AC:

AN:

2644

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5952

Middle Eastern (MID)

AF:

0.00

AC:

AN:

237

European-Non Finnish (NFE)

AF:

0.000113

AC:

AN:

53037

Other (OTH)

AF:

0.00

AC:

AN:

1491

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.0000868

Hom.:

Bravo

AF:

0.0000642

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:2

Dec 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PDHA1: BS2 -

Oct 12, 2022

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

See Variant Classification Assertion Criteria. -

not specified

Uncertain:1

Nov 25, 2015

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

Sep 02, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Benign:1

Dec 10, 2021

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

Mar 26, 2020

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

PhyloP100

7.2

Mutation Taster

=90/10

polymorphism

(source)

Splicing

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