rs201754585

chrX-19355339-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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:4
• Conservation: PhyloP100: -1.05

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]

ACMG classification

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 GnomAd at 35 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PDHA1	NM_000284.4	c.604-10C>T		splice_polypyrimidine_tract_variant, intron_variant		ENST00000422285.7

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.000824 AC: 93 AN: 112839 Hom.: 1 Cov.: 24 AF XY: 0.00100 AC XY: 35 AN XY: 34989

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.: 0 AF XY: 0.00296 AC XY: 201 AN XY: 67803

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.: 6 Cov.: 31 AF XY: 0.00185 AC XY: 672 AN XY: 362297

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: 93 AN: 112893 Hom.: 1 Cov.: 24 AF XY: 0.000998 AC XY: 35 AN XY: 35053

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.: 9

Bravo AF: 0.000722

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

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	Invitae	Jan 31, 2024	- -
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. -

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

Other links and lift over

dbSNP: rs201754585; hg19: chrX-19373457;