rs754393427

Positions:

• chrX-19346494-AT-A
• chrX-19346494-AT-ATT
• chrX-19346494-AT-ATTT

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS1

The NM_000284.4(PDHA1):​c.57+2410del variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00157 in 410,344 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0000092 (0 hom., 0 hem., cov: 23)
  • Exomes 𝑓: 0.0021 (0 hom. 1 hem.)
• Consequence: PDHA1 NM_000284.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.286

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 Likely_benign. Variant got -4 ACMG points.

• BS1: Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.00213 (642/301791) while in subpopulation SAS AF= 0.00304 (61/20069). AF 95% confidence interval is 0.00243. There are 0 homozygotes in gnomad4_exome. There are 1 alleles in male gnomad4_exome subpopulation. Median coverage is 4. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PDHA1	NM_000284.4	c.57+2410del		intron_variant		ENST00000422285.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PDHA1	ENST00000422285.7	c.57+2410del		intron_variant		1	NM_000284.4	P1

Frequencies

GnomAD3 genomes AF: 0.00000921 AC: 1 AN: 108553 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 31551

Gnomad AFR AF: 0.0000336

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00213 AC: 642 AN: 301791 Hom.: 0 Cov.: 4 AF XY: 0.0000108 AC XY: 1 AN XY: 92199

Gnomad4 AFR exome AF: 0.00177

Gnomad4 AMR exome AF: 0.00285

Gnomad4 ASJ exome AF: 0.00145

Gnomad4 EAS exome AF: 0.000978

Gnomad4 SAS exome AF: 0.00304

Gnomad4 FIN exome AF: 0.00129

Gnomad4 NFE exome AF: 0.00222

Gnomad4 OTH exome AF: 0.00211

GnomAD4 genome AF: 0.00000921 AC: 1 AN: 108553 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 31551

Gnomad4 AFR AF: 0.0000336

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00509 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

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: rs754393427; hg19: chrX-19364612;