rs145749914

Positions:

• chrX-19346576-G-A

Variant summary

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

The ENST00000422285.7(PDHA1):​c.57+2482G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00418 in 867,742 control chromosomes in the GnomAD database, including 97 homozygotes. There are 916 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.019 (61 hom., 584 hem., cov: 23)
  • Exomes 𝑓: 0.0019 (36 hom. 332 hem.)
• Consequence: PDHA1 ENST00000422285.7 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.568

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 (MetaRNN=0.0022673607).
• BP6: Variant X-19346576-G-A is Benign according to our data. Variant chrX-19346576-G-A is described in ClinVar as [Benign]. Clinvar id is 377151.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-19346576-G-A is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0636 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PDHA1	NM_000284.4	c.57+2482G>A		intron_variant		ENST00000422285.7	NP_000275.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PDHA1	ENST00000422285.7	c.57+2482G>A		intron_variant		1	NM_000284.4	ENSP00000394382	P1

Frequencies

GnomAD3 genomes AF: 0.0193 AC: 2161 AN: 111771 Hom.: 61 Cov.: 23 AF XY: 0.0171 AC XY: 583 AN XY: 33995

Gnomad AFR AF: 0.0661

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00864

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00195

Gnomad SAS AF: 0.000736

Gnomad FIN AF: 0.000165

Gnomad MID AF: 0.00418

Gnomad NFE AF: 0.000320

Gnomad OTH AF: 0.0125

GnomAD3 exomes AF: 0.00205 AC: 106 AN: 51768 Hom.: 1 AF XY: 0.000314 AC XY: 3 AN XY: 9544

Gnomad AFR exome AF: 0.0487

Gnomad AMR exome AF: 0.00244

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00255

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000232

Gnomad OTH exome AF: 0.00308

GnomAD4 exome AF: 0.00194 AC: 1466 AN: 755919 Hom.: 36 Cov.: 11 AF XY: 0.00177 AC XY: 332 AN XY: 187189

Gnomad4 AFR exome AF: 0.0611

Gnomad4 AMR exome AF: 0.00429

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00229

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000175

Gnomad4 OTH exome AF: 0.00567

GnomAD4 genome AF: 0.0194 AC: 2164 AN: 111823 Hom.: 61 Cov.: 23 AF XY: 0.0171 AC XY: 584 AN XY: 34057

Gnomad4 AFR AF: 0.0660

Gnomad4 AMR AF: 0.00863

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00195

Gnomad4 SAS AF: 0.000738

Gnomad4 FIN AF: 0.000165

Gnomad4 NFE AF: 0.000320

Gnomad4 OTH AF: 0.0124

Alfa AF: 0.00747 Hom.: 45

Bravo AF: 0.0218

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.00292 AC: 48

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	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jan 05, 2017	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 09, 2015

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	1.7
DANN	Benign	0.81
DEOGEN2	Benign	0.0072	.;T
FATHMM_MKL	Benign	0.019	N
LIST_S2	Benign	0.42	T;T
MetaRNN	Benign	0.0023	T;T
MetaSVM	Uncertain	0.28	D
MutationTaster	Benign	1.0	P;P;P;P;P
PrimateAI	Benign	0.43	T
PROVEAN	Benign	0.43	N;N
REVEL	Benign	0.24
Sift	Benign	0.10	T;T
Sift4G	Benign	0.30	T;T
Vest4		0.10
MVP		0.52
MPC		1.3
ClinPred		0.0078	T
GERP RS		0.43
gMVP		0.26

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: rs145749914; hg19: chrX-19364694;