X-19346494-AT-ATT

Variant names:

• chrX-19346494-A-AT
• rs754393427
• NM_000284.4:c.57+2410dupT

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_001173454.2(PDHA1):​c.58-6dupT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00565 in 411,968 control chromosomes in the GnomAD database, including 19 homozygotes. There are 533 hemizygotes in GnomAD. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0062 (3 hom., 183 hem., cov: 23)
  • Exomes 𝑓: 0.0055 (16 hom. 350 hem.)
• Consequence: PDHA1 NM_001173454.2 splice_region, intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• 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 Benign. Variant got -16 ACMG points.

• BP6: Variant X-19346494-A-AT is Benign according to our data. Variant chrX-19346494-A-AT is described in ClinVar as [Likely_benign]. Clinvar id is 445393.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00621 (674/108600) while in subpopulation SAS AF= 0.0419 (107/2555). AF 95% confidence interval is 0.0354. There are 3 homozygotes in gnomad4. There are 183 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 3 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PDHA1	NM_000284.4	c.57+2410dupT		intron_variant	Intron 1 of 10	ENST00000422285.7	NP_000275.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PDHA1	ENST00000422285.7	c.57+2400_57+2401insT		intron_variant	Intron 1 of 10	1	NM_000284.4	ENSP00000394382.2

Frequencies

GnomAD3 genomes AF: 0.00617 AC: 670 AN: 108558 Hom.: 3 Cov.: 23 AF XY: 0.00567 AC XY: 179 AN XY: 31558

Gnomad AFR AF: 0.0135

Gnomad AMI AF: 0.0271

Gnomad AMR AF: 0.00306

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00114

Gnomad SAS AF: 0.0420

Gnomad FIN AF: 0.00214

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00169

Gnomad OTH AF: 0.00479

GnomAD4 exome AF: 0.00546 AC: 1655 AN: 303368 Hom.: 16 Cov.: 4 AF XY: 0.00377 AC XY: 350 AN XY: 92854

Gnomad4 AFR exome AF: 0.0128

Gnomad4 AMR exome AF: 0.00427

Gnomad4 ASJ exome AF: 0.00136

Gnomad4 EAS exome AF: 0.00123

Gnomad4 SAS exome AF: 0.0351

Gnomad4 FIN exome AF: 0.00305

Gnomad4 NFE exome AF: 0.00312

Gnomad4 OTH exome AF: 0.00442

GnomAD4 genome AF: 0.00621 AC: 674 AN: 108600 Hom.: 3 Cov.: 23 AF XY: 0.00579 AC XY: 183 AN XY: 31610

Gnomad4 AFR AF: 0.0136

Gnomad4 AMR AF: 0.00306

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00115

Gnomad4 SAS AF: 0.0419

Gnomad4 FIN AF: 0.00214

Gnomad4 NFE AF: 0.00169

Gnomad4 OTH AF: 0.00473

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jan 22, 2022

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

See Variant Classification Assertion Criteria. -

May 04, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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;