chrX-19360497-A-G

Position:

• chrX-19360497-A-G

Variant summary

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

The NM_001001671.4(MAP3K15):​c.*252T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.128 in 282,893 control chromosomes in the GnomAD database, including 6,084 homozygotes. There are 10,491 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 (5035 hom., 6749 hem., cov: 23)
  • Exomes 𝑓: 0.070 (1049 hom. 3742 hem.)
• Consequence: MAP3K15 NM_001001671.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.02

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=-0.95).
• BP6: Variant X-19360497-A-G is Benign according to our data. Variant chrX-19360497-A-G is described in ClinVar as [Benign]. Clinvar id is 914464.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.651 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PDHA1	NM_000284.4	c.*844A>G		3_prime_UTR_variant	11/11	ENST00000422285.7
MAP3K15	NM_001001671.4	c.*252T>C		3_prime_UTR_variant	29/29	ENST00000338883.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAP3K15	ENST00000338883.9	c.*252T>C		3_prime_UTR_variant	29/29	5	NM_001001671.4	P1
PDHA1	ENST00000422285.7	c.*844A>G		3_prime_UTR_variant	11/11	1	NM_000284.4	P1

Frequencies

GnomAD3 genomes AF: 0.216 AC: 24126 AN: 111516 Hom.: 5032 Cov.: 23 AF XY: 0.199 AC XY: 6710 AN XY: 33734

Gnomad AFR AF: 0.658

Gnomad AMI AF: 0.111

Gnomad AMR AF: 0.0974

Gnomad ASJ AF: 0.112

Gnomad EAS AF: 0.00474

Gnomad SAS AF: 0.137

Gnomad FIN AF: 0.0297

Gnomad MID AF: 0.200

Gnomad NFE AF: 0.0345

Gnomad OTH AF: 0.199

GnomAD4 exome AF: 0.0704 AC: 12059 AN: 171323 Hom.: 1049 Cov.: 0 AF XY: 0.0786 AC XY: 3742 AN XY: 47597

Gnomad4 AFR exome AF: 0.631

Gnomad4 AMR exome AF: 0.0781

Gnomad4 ASJ exome AF: 0.105

Gnomad4 EAS exome AF: 0.00538

Gnomad4 SAS exome AF: 0.150

Gnomad4 FIN exome AF: 0.0353

Gnomad4 NFE exome AF: 0.0364

Gnomad4 OTH exome AF: 0.0949

GnomAD4 genome AF: 0.217 AC: 24172 AN: 111570 Hom.: 5035 Cov.: 23 AF XY: 0.200 AC XY: 6749 AN XY: 33798

Gnomad4 AFR AF: 0.658

Gnomad4 AMR AF: 0.0973

Gnomad4 ASJ AF: 0.112

Gnomad4 EAS AF: 0.00476

Gnomad4 SAS AF: 0.139

Gnomad4 FIN AF: 0.0297

Gnomad4 NFE AF: 0.0345

Gnomad4 OTH AF: 0.196

Alfa AF: 0.0993 Hom.: 2018

Bravo AF: 0.244

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	-0.95
CADD	Benign	1.4
DANN	Benign	0.33

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: rs1042453; hg19: chrX-19378615;