chrX-19361030-G-A

Position:

• chrX-19361030-G-A

Variant summary

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

The NM_000284.4(PDHA1):​c.*1377G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.104 in 420,027 control chromosomes in the GnomAD database, including 5,723 homozygotes. There are 13,772 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (4035 hom., 6649 hem., cov: 25)
  • Exomes 𝑓: 0.069 (1688 hom. 7123 hem.)
• Consequence: PDHA1 NM_000284.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.239

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]

MAP3K15 (HGNC:31689): (mitogen-activated protein kinase kinase kinase 15) The protein encoded by this gene is a member of the mitogen-activated protein kinase (MAPK) family. These family members function in a protein kinase signal transduction cascade, where an activated MAPK kinase kinase (MAP3K) phosphorylates and activates a specific MAPK kinase (MAP2K), which then activates a specific MAPK. This MAP3K protein plays an essential role in apoptotic cell death triggered by cellular stresses. [provided by RefSeq, Jul 2010]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant X-19361030-G-A is Benign according to our data. Variant chrX-19361030-G-A is described in ClinVar as [Benign]. Clinvar id is 913015.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.583 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PDHA1	NM_000284.4	c.*1377G>A		3_prime_UTR_variant	11/11	ENST00000422285.7
MAP3K15	NM_001001671.4	c.3858-197C>T		intron_variant		ENST00000338883.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PDHA1	ENST00000422285.7	c.*1377G>A		3_prime_UTR_variant	11/11	1	NM_000284.4	P1
MAP3K15	ENST00000338883.9	c.3858-197C>T		intron_variant		5	NM_001001671.4	P1

Frequencies

GnomAD3 genomes AF: 0.198 AC: 22403 AN: 112918 Hom.: 4033 Cov.: 25 AF XY: 0.189 AC XY: 6615 AN XY: 35084

Gnomad AFR AF: 0.590

Gnomad AMI AF: 0.113

Gnomad AMR AF: 0.0909

Gnomad ASJ AF: 0.112

Gnomad EAS AF: 0.00443

Gnomad SAS AF: 0.140

Gnomad FIN AF: 0.0306

Gnomad MID AF: 0.203

Gnomad NFE AF: 0.0344

Gnomad OTH AF: 0.183

GnomAD4 exome AF: 0.0687 AC: 21109 AN: 307057 Hom.: 1688 Cov.: 4 AF XY: 0.0730 AC XY: 7123 AN XY: 97629

Gnomad4 AFR exome AF: 0.595

Gnomad4 AMR exome AF: 0.0810

Gnomad4 ASJ exome AF: 0.110

Gnomad4 EAS exome AF: 0.00572

Gnomad4 SAS exome AF: 0.155

Gnomad4 FIN exome AF: 0.0373

Gnomad4 NFE exome AF: 0.0379

Gnomad4 OTH exome AF: 0.0992

GnomAD4 genome AF: 0.199 AC: 22442 AN: 112970 Hom.: 4035 Cov.: 25 AF XY: 0.189 AC XY: 6649 AN XY: 35146

Gnomad4 AFR AF: 0.590

Gnomad4 AMR AF: 0.0908

Gnomad4 ASJ AF: 0.112

Gnomad4 EAS AF: 0.00445

Gnomad4 SAS AF: 0.141

Gnomad4 FIN AF: 0.0306

Gnomad4 NFE AF: 0.0344

Gnomad4 OTH AF: 0.180

Alfa AF: 0.192 Hom.: 1365

Bravo AF: 0.221

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Pyruvate dehydrogenase E1-alpha deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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. -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.51
DANN	Benign	0.63

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: rs56039350; hg19: chrX-19379148;