rs201754585

Positions:

chrX-19355339-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000284.4(PDHA1):c.604-10C>T variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00122 in 1,209,772 control chromosomes in the GnomAD database, including 7 homozygotes. There are 707 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.00082 ( 1 hom., 35 hem., cov: 24)

Exomes 𝑓: 0.0013 ( 6 hom. 672 hem. )

Consequence

PDHA1
NM_000284.4 splice_polypyrimidine_tract, intron

Scores

Splicing: ADA: 0.00001065

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -1.05

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.77).

BP6

Variant X-19355339-C-T is Benign according to our data. Variant chrX-19355339-C-T is described in ClinVar as [Benign]. Clinvar id is 214930.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-19355339-C-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000824 (93/112893) while in subpopulation SAS AF= 0.0109 (30/2759). AF 95% confidence interval is 0.00783. There are 1 homozygotes in gnomad4. There are 35 alleles in male gnomad4 subpopulation. Median coverage is 24. This position pass quality control queck.

BS2

High Hemizygotes in GnomAd4 at 35 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PDHA1	NM_000284.4 linkuse as main transcript	c.604-10C>T		splice_polypyrimidine_tract_variant, intron_variant		ENST00000422285.7	NP_000275.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PDHA1	ENST00000422285.7 linkuse as main transcript	c.604-10C>T		splice_polypyrimidine_tract_variant, intron_variant		1	NM_000284.4	ENSP00000394382	P1	P08559-1

Frequencies

GnomAD3 genomes

AF:

0.000824

AC:

AN:

112839

Hom.:

Cov.:

AF XY:

0.00100

AC XY:

AN XY:

34989

show subpopulations

Gnomad AFR

AF:

0.0000966

Gnomad AMI

AF:

0.00146

Gnomad AMR

AF:

0.000469

Gnomad ASJ

AF:

0.00566

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0108

Gnomad FIN

AF:

0.000321

Gnomad MID

AF:

0.0126

Gnomad NFE

AF:

0.000561

Gnomad OTH

AF:

0.00264

GnomAD3 exomes

AF:

0.00209

AC:

383

AN:

183357

Hom.:

AF XY:

0.00296

AC XY:

201

AN XY:

67803

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000365

Gnomad ASJ exome

AF:

0.00441

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0137

Gnomad FIN exome

AF:

0.000250

Gnomad NFE exome

AF:

0.000734

Gnomad OTH exome

AF:

0.00331

GnomAD4 exome

AF:

0.00126

AC:

1385

AN:

1096879

Hom.:

Cov.:

AF XY:

0.00185

AC XY:

672

AN XY:

362297

show subpopulations

Gnomad4 AFR exome

AF:

0.000303

Gnomad4 AMR exome

AF:

0.000511

Gnomad4 ASJ exome

AF:

0.00465

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0145

Gnomad4 FIN exome

AF:

0.000444

Gnomad4 NFE exome

AF:

0.000405

Gnomad4 OTH exome

AF:

0.00180

GnomAD4 genome

AF:

0.000824

AC:

AN:

112893

Hom.:

Cov.:

AF XY:

0.000998

AC XY:

AN XY:

35053

show subpopulations

Gnomad4 AFR

AF:

0.0000964

Gnomad4 AMR

AF:

0.000468

Gnomad4 ASJ

AF:

0.00566

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.0109

Gnomad4 FIN

AF:

0.000321

Gnomad4 NFE

AF:

0.000562

Gnomad4 OTH

AF:

0.00261

Alfa

AF:

0.00127

Hom.:

Bravo

AF:

0.000722

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jul 28, 2016	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 04, 2012	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. -

Pyruvate dehydrogenase E1-alpha deficiency

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.77

CADD

Benign

0.034

DANN

Benign

0.85

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000011

dbscSNV1_RF

Benign

0.012

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

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