X-19361047-C-T

Position:

• chrX-19361047-C-T

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.*1394C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.111 in 417,955 control chromosomes in the GnomAD database, including 6,968 homozygotes. There are 14,577 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.22 (5002 hom., 7281 hem., cov: 25)
  • Exomes 𝑓: 0.071 (1966 hom. 7296 hem.)
• Consequence: PDHA1 NM_000284.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -4.43

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=-0.94).
• BP6: Variant X-19361047-C-T is Benign according to our data. Variant chrX-19361047-C-T is described in ClinVar as [Benign]. Clinvar id is 913016.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.65 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PDHA1	NM_000284.4	c.*1394C>T		3_prime_UTR_variant	11/11	ENST00000422285.7
MAP3K15	NM_001001671.4	c.3858-214G>A		intron_variant		ENST00000338883.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PDHA1	ENST00000422285.7	c.*1394C>T		3_prime_UTR_variant	11/11	1	NM_000284.4	P1
MAP3K15	ENST00000338883.9	c.3858-214G>A		intron_variant		5	NM_001001671.4	P1

Frequencies

GnomAD3 genomes AF: 0.218 AC: 24617 AN: 112984 Hom.: 4999 Cov.: 25 AF XY: 0.206 AC XY: 7245 AN XY: 35150

Gnomad AFR AF: 0.657

Gnomad AMI AF: 0.114

Gnomad AMR AF: 0.0986

Gnomad ASJ AF: 0.112

Gnomad EAS AF: 0.00441

Gnomad SAS AF: 0.142

Gnomad FIN AF: 0.0311

Gnomad MID AF: 0.210

Gnomad NFE AF: 0.0347

Gnomad OTH AF: 0.199

GnomAD4 exome AF: 0.0713 AC: 21735 AN: 304920 Hom.: 1966 Cov.: 4 AF XY: 0.0752 AC XY: 7296 AN XY: 97038

Gnomad4 AFR exome AF: 0.656

Gnomad4 AMR exome AF: 0.0878

Gnomad4 ASJ exome AF: 0.110

Gnomad4 EAS exome AF: 0.00560

Gnomad4 SAS exome AF: 0.154

Gnomad4 FIN exome AF: 0.0377

Gnomad4 NFE exome AF: 0.0381

Gnomad4 OTH exome AF: 0.105

GnomAD4 genome AF: 0.218 AC: 24660 AN: 113035 Hom.: 5002 Cov.: 25 AF XY: 0.207 AC XY: 7281 AN XY: 35211

Gnomad4 AFR AF: 0.657

Gnomad4 AMR AF: 0.0985

Gnomad4 ASJ AF: 0.112

Gnomad4 EAS AF: 0.00442

Gnomad4 SAS AF: 0.143

Gnomad4 FIN AF: 0.0311

Gnomad4 NFE AF: 0.0347

Gnomad4 OTH AF: 0.196

Alfa AF: 0.144 Hom.: 996

Bravo AF: 0.243

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	-0.94
CADD	Benign	0.17
DANN	Benign	0.64

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: rs55856360; hg19: chrX-19379165;