X-19343940-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_000284.4(PDHA1):c.-98C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00221 in 769,819 control chromosomes in the GnomAD database, including 3 homozygotes. There are 474 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0018 (0 hom., 57 hem., cov: 24)
  • Exomes 𝑓: 0.0023 (3 hom. 417 hem.)
• Consequence: PDHA1 NM_000284.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.140

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BP6: Variant X-19343940-C-T is Benign according to our data. Variant chrX-19343940-C-T is described in ClinVar as [Benign]. Clinvar id is 914924.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00184 (208/112896) while in subpopulation NFE AF= 0.00267 (142/53210). AF 95% confidence interval is 0.00231. There are 0 homozygotes in gnomad4. There are 57 alleles in male gnomad4 subpopulation. Median coverage is 24. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd at 57 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PDHA1	NM_000284.4	c.-98C>T		5_prime_UTR_variant	1/11	ENST00000422285.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PDHA1	ENST00000422285.7	c.-98C>T		5_prime_UTR_variant	1/11	1	NM_000284.4	P1

Frequencies

GnomAD3 genomes AF: 0.00184 AC: 208 AN: 112843 Hom.: 0 Cov.: 24 AF XY: 0.00163 AC XY: 57 AN XY: 34985

Gnomad AFR AF: 0.000417

Gnomad AMI AF: 0.00734

Gnomad AMR AF: 0.00241

Gnomad ASJ AF: 0.00377

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000804

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00267

Gnomad OTH AF: 0.00459

GnomAD4 exome AF: 0.00227 AC: 1494 AN: 656923 Hom.: 3 Cov.: 11 AF XY: 0.00217 AC XY: 417 AN XY: 191727

Gnomad4 AFR exome AF: 0.000600

Gnomad4 AMR exome AF: 0.00222

Gnomad4 ASJ exome AF: 0.00322

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000861

Gnomad4 NFE exome AF: 0.00280

Gnomad4 OTH exome AF: 0.00204

GnomAD4 genome AF: 0.00184 AC: 208 AN: 112896 Hom.: 0 Cov.: 24 AF XY: 0.00163 AC XY: 57 AN XY: 35048

Gnomad4 AFR AF: 0.000416

Gnomad4 AMR AF: 0.00240

Gnomad4 ASJ AF: 0.00377

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000804

Gnomad4 NFE AF: 0.00267

Gnomad4 OTH AF: 0.00453

Alfa AF: 0.00235 Hom.: 11

Bravo AF: 0.00197

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Pyruvate dehydrogenase E1-alpha deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
Cadd	Benign	13
Dann	Benign	0.88
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs192773464; hg19: chrX-19362058;