chrX-19343950-G-A

Position:

• chrX-19343950-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000284.4(PDHA1):​c.-88G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0344 in 857,001 control chromosomes in the GnomAD database, including 549 homozygotes. There are 10,309 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.038 (96 hom., 1354 hem., cov: 24)
  • Exomes 𝑓: 0.034 (453 hom. 8955 hem.)
• Consequence: PDHA1 NM_000284.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.334

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=-0.75).
• BP6: Variant X-19343950-G-A is Benign according to our data. Variant chrX-19343950-G-A is described in ClinVar as [Benign]. Clinvar id is 914925.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-19343950-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.117 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PDHA1	NM_000284.4	c.-88G>A		5_prime_UTR_variant	1/11	ENST00000422285.7	NP_000275.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PDHA1	ENST00000422285.7	c.-88G>A		5_prime_UTR_variant	1/11	1	NM_000284.4	ENSP00000394382	P1

Frequencies

GnomAD3 genomes AF: 0.0379 AC: 4277 AN: 112702 Hom.: 97 Cov.: 24 AF XY: 0.0386 AC XY: 1347 AN XY: 34886

Gnomad AFR AF: 0.0662

Gnomad AMI AF: 0.113

Gnomad AMR AF: 0.0190

Gnomad ASJ AF: 0.0708

Gnomad EAS AF: 0.00505

Gnomad SAS AF: 0.127

Gnomad FIN AF: 0.0191

Gnomad MID AF: 0.101

Gnomad NFE AF: 0.0221

Gnomad OTH AF: 0.0395

GnomAD4 exome AF: 0.0339 AC: 25198 AN: 744246 Hom.: 453 Cov.: 12 AF XY: 0.0424 AC XY: 8955 AN XY: 211270

Gnomad4 AFR exome AF: 0.0754

Gnomad4 AMR exome AF: 0.0179

Gnomad4 ASJ exome AF: 0.0693

Gnomad4 EAS exome AF: 0.00459

Gnomad4 SAS exome AF: 0.142

Gnomad4 FIN exome AF: 0.0249

Gnomad4 NFE exome AF: 0.0245

Gnomad4 OTH exome AF: 0.0383

GnomAD4 genome AF: 0.0380 AC: 4281 AN: 112755 Hom.: 96 Cov.: 24 AF XY: 0.0387 AC XY: 1354 AN XY: 34949

Gnomad4 AFR AF: 0.0663

Gnomad4 AMR AF: 0.0190

Gnomad4 ASJ AF: 0.0708

Gnomad4 EAS AF: 0.00507

Gnomad4 SAS AF: 0.127

Gnomad4 FIN AF: 0.0191

Gnomad4 NFE AF: 0.0221

Gnomad4 OTH AF: 0.0390

Alfa AF: 0.0297 Hom.: 537

Bravo AF: 0.0397

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Pyruvate dehydrogenase E1-alpha deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	7.0
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)		0.0		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: rs5955751; hg19: chrX-19362068;