rs754393427

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_001173454.2(PDHA1):​c.58-6delT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00157 in 410,344 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. 1/1 splice prediction tools predict no significant impact on normal splicing. 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_001173454.2 splice_region, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.286
• Publications: 0 publications found

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]

PDHA1 Gene-Disease associations (from GenCC):

• Leigh syndrome

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
• pyruvate dehydrogenase E1-alpha deficiency

  Inheritance: XL, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet, Ambry Genetics
• Leigh syndrome with leukodystrophy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001173454.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDHA1	NM_000284.4	MANE Select	c.57+2410delT		intron	N/A	NP_000275.1
	PDHA1	NM_001173454.2		c.58-6delT		splice_region intron	N/A	NP_001166925.1
	PDHA1	NM_001173455.2		c.57+2410delT		intron	N/A	NP_001166926.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDHA1	ENST00000422285.7	TSL:1 MANE Select	c.57+2401delT		intron	N/A	ENSP00000394382.2
	PDHA1	ENST00000947567.1		c.142-15delT		intron	N/A	ENSP00000617626.1
	PDHA1	ENST00000947577.1		c.58-15delT		intron	N/A	ENSP00000617636.1

Frequencies

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

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

GnomAD2 exomes AF: 0.00662 AC: 239 AN: 36099 AF XY: 0.00

Gnomad AFR exome AF: 0.00801

Gnomad AMR exome AF: 0.00610

Gnomad ASJ exome AF: 0.00468

Gnomad EAS exome AF: 0.00592

Gnomad FIN exome AF: 0.00542

Gnomad NFE exome AF: 0.00716

Gnomad OTH exome AF: 0.00444

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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00177 AC: 14 AN: 7922

American (AMR) AF: 0.00285 AC: 57 AN: 19970

Ashkenazi Jewish (ASJ) AF: 0.00145 AC: 16 AN: 11006

East Asian (EAS) AF: 0.000978 AC: 19 AN: 19424

South Asian (SAS) AF: 0.00304 AC: 61 AN: 20069

European-Finnish (FIN) AF: 0.00129 AC: 27 AN: 20906

Middle Eastern (MID) AF: 0.00245 AC: 6 AN: 2448

European-Non Finnish (NFE) AF: 0.00222 AC: 405 AN: 182525

Other (OTH) AF: 0.00211 AC: 37 AN: 17521

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

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

African (AFR) AF: 0.0000336 AC: 1 AN: 29791

American (AMR) AF: 0.00 AC: 0 AN: 10118

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2582

East Asian (EAS) AF: 0.00 AC: 0 AN: 3504

South Asian (SAS) AF: 0.00 AC: 0 AN: 2568

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5598

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 233

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 52033

Other (OTH) AF: 0.00 AC: 0 AN: 1461

Alfa AF: 0.00509 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.29
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs754393427; hg19: chrX-19364612; COSMIC: COSV63327848;