rs762505127

chrX-19359651-TAAGGGG-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The NM_000284.4(PDHA1):c.1173_*5del variant causes a stop retained, 3 prime UTR change. The variant allele was found at a frequency of 0.0000655 in 1,205,774 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 22 hemizygotes in GnomAD. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000063 (0 hom., 2 hem., cov: 22)
  • Exomes 𝑓: 0.000066 (0 hom. 20 hem.)
• Consequence: PDHA1 NM_000284.4 stop_retained, 3_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 7.16

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 -9 ACMG points.

• BP6: Variant X-19359651-TAAGGGG-T is Benign according to our data. Variant chrX-19359651-TAAGGGG-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 421578.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=3, Benign=1}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000063 (7/111140) while in subpopulation NFE AF= 0.000113 (6/53037). AF 95% confidence interval is 0.0000485. There are 0 homozygotes in gnomad4. There are 2 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PDHA1	NM_000284.4	c.1173_*5del		stop_retained_variant, 3_prime_UTR_variant	11/11	ENST00000422285.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PDHA1	ENST00000422285.7	c.1173_*5del		stop_retained_variant, 3_prime_UTR_variant	11/11	1	NM_000284.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000630 AC: 7 AN: 111140 Hom.: 0 Cov.: 22 AF XY: 0.0000600 AC XY: 2 AN XY: 33356

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000966

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: 0.000113

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000654 AC: 12 AN: 183377 Hom.: 0 AF XY: 0.000118 AC XY: 8 AN XY: 67813

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000365

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000134

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000658 AC: 72 AN: 1094634 Hom.: 0 AF XY: 0.0000555 AC XY: 20 AN XY: 360062

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000858

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000630 AC: 7 AN: 111140 Hom.: 0 Cov.: 22 AF XY: 0.0000600 AC XY: 2 AN XY: 33356

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000966

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000113

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000868 Hom.: 1

Bravo AF: 0.0000642

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2023	PDHA1: BS2 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 12, 2022	See Variant Classification Assertion Criteria. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Nov 25, 2015

- -

Pyruvate dehydrogenase E1-alpha deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Sep 29, 2023

- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 10, 2021

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Pyruvate dehydrogenase complex deficiency Benign:1

Likely benign, no assertion criteria provided

clinical testing

Natera, Inc.

Mar 26, 2020

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs762505127; hg19: chrX-19377769;