chrX-19343940-C-T

Position:

chrX-19343940-C-T

Variant summary

Our verdict is Benign. Variant got -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

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id 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 male gnomad4 subpopulation. Median coverage is 24. This position pass quality control queck.

BS2

High Hemizygotes in GnomAd4 at 57 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PDHA1	NM_000284.4 linkuse as main transcript	c.-98C>T		5_prime_UTR_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.-98C>T		5_prime_UTR_variant	1/11	1	NM_000284.4	P1	P08559-1

Frequencies

GnomAD3 genomes

AF:

0.00184

AC:

208

AN:

112843

Hom.:

Cov.:

AF XY:

0.00163

AC XY:

AN XY:

34985

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

Gnomad4 AFR exome

AF:

0.000600

Gnomad4 AMR exome

AF:

0.00222

Gnomad4 ASJ exome

AF:

0.00322

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000861

Gnomad4 NFE exome

AF:

0.00280

Gnomad4 OTH exome

AF:

0.00204

GnomAD4 genome

AF:

0.00184

AC:

208

AN:

112896

Hom.:

Cov.:

AF XY:

0.00163

AC XY:

AN XY:

35048

show subpopulations

Gnomad4 AFR

AF:

0.000416

Gnomad4 AMR

AF:

0.00240

Gnomad4 ASJ

AF:

0.00377

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000804

Gnomad4 NFE

AF:

0.00267

Gnomad4 OTH

AF:

0.00453

Alfa

AF:

0.00235

Hom.:

Bravo

AF:

0.00197

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Pyruvate dehydrogenase E1-alpha deficiency

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.71

CADD

Benign

DANN

Benign

0.88

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

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

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