Genetic Variant PDHA1:c.-98C>T (chrX-19343940-C-T) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_000284.4(PDHA1):c.-98C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00221 in 769,819 control chromosomes in the GnomAD database, including 3 homozygotes. There are 474 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0018 ( 0 hom., 57 hem., cov: 24)

Exomes 𝑓: 0.0023 ( 3 hom. 417 hem. )

Consequence

PDHA1
NM_000284.4 5_prime_UTR

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.140

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):

pyruvate dehydrogenase E1-alpha deficiency
Inheritance: AR, XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Genomics England PanelApp, G2P, Orphanet, Labcorp Genetics (formerly Invitae)
Leigh syndrome
Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
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=-0.71).

BP6

Variant X-19343940-C-T is Benign according to our data. Variant chrX-19343940-C-T is described in ClinVar as Benign. ClinVar VariationId is 914924.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00184 (208/112896) while in subpopulation NFE AF = 0.00267 (142/53210). AF 95% confidence interval is 0.00231. There are 0 homozygotes in GnomAd4. There are 57 alleles in the male GnomAd4 subpopulation. Median coverage is 24. This position passed quality control check.

BS2

High Hemizygotes in GnomAd4 at 57 XL,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000284.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
PDHA1	NM_000284.4	MANE Select	c.-98C>T	5_prime_UTR	Exon 1 of 11	NP_000275.1	P08559-1
PDHA1	NM_001173454.2		c.-98C>T	5_prime_UTR	Exon 1 of 12	NP_001166925.1	P08559-4
PDHA1	NM_001173455.2		c.-98C>T	5_prime_UTR	Exon 1 of 11	NP_001166926.1	P08559-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
PDHA1	ENST00000422285.7	TSL:1 MANE Select	c.-98C>T	5_prime_UTR	Exon 1 of 11	ENSP00000394382.2	P08559-1
PDHA1	ENST00000947567.1		c.-98C>T	5_prime_UTR	Exon 1 of 13	ENSP00000617626.1
PDHA1	ENST00000881112.1		c.-98C>T	5_prime_UTR	Exon 1 of 12	ENSP00000551171.1

Frequencies

GnomAD3 genomes

AF:

0.00184

AC:

208

AN:

112843

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000417

Gnomad AMI

AF:

0.00734

Gnomad AMR

AF:

0.00241

Gnomad ASJ

AF:

0.00377

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000804

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00267

Gnomad OTH

AF:

0.00459

GnomAD4 exome

AF:

0.00227

AC:

1494

AN:

656923

Hom.:

Cov.:

AF XY:

0.00217

AC XY:

417

AN XY:

191727

show subpopulations

African (AFR)

AF:

0.000600

AC:

AN:

18325

American (AMR)

AF:

0.00222

AC:

AN:

29732

Ashkenazi Jewish (ASJ)

AF:

0.00322

AC:

AN:

16148

East Asian (EAS)

AF:

0.00

AC:

AN:

27429

South Asian (SAS)

AF:

0.00

AC:

AN:

43367

European-Finnish (FIN)

AF:

0.000861

AC:

AN:

34858

Middle Eastern (MID)

AF:

0.00139

AC:

AN:

2165

European-Non Finnish (NFE)

AF:

0.00280

AC:

1268

AN:

453478

Other (OTH)

AF:

0.00204

AC:

AN:

31421

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

119

178

238

297

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

160

200

<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:

0.00184

AC:

208

AN:

112896

Hom.:

Cov.:

AF XY:

0.00163

AC XY:

AN XY:

35048

show subpopulations

African (AFR)

AF:

0.000416

AC:

AN:

31221

American (AMR)

AF:

0.00240

AC:

AN:

10820

Ashkenazi Jewish (ASJ)

AF:

0.00377

AC:

AN:

2651

East Asian (EAS)

AF:

0.00

AC:

AN:

3544

South Asian (SAS)

AF:

0.00

AC:

AN:

2790

European-Finnish (FIN)

AF:

0.000804

AC:

AN:

6220

Middle Eastern (MID)

AF:

0.00

AC:

AN:

215

European-Non Finnish (NFE)

AF:

0.00267

AC:

142

AN:

53210

Other (OTH)

AF:

0.00453

AC:

AN:

1544

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.516

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.00235

Hom.:

Bravo

AF:

0.00197

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Pyruvate dehydrogenase E1-alpha deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.71

CADD

Benign

(source)

DANN

Benign

0.88

PhyloP100

0.14

PromoterAI

0.067

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

Mutation Taster

=300/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over