chrX-19360267-G-T

Position:

• chrX-19360267-G-T

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.*482C>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 0.0572 in 134,872 control chromosomes in the GnomAD database, including 325 homozygotes. There are 2,302 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.063 (311 hom., 2124 hem., cov: 24)
  • Exomes 𝑓: 0.029 (14 hom. 178 hem.)
• Consequence: MAP3K15 NM_001001671.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.160

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-19360267-G-T is Benign according to our data. Variant chrX-19360267-G-T is described in ClinVar as [Benign]. Clinvar id is 914460.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.149 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PDHA1	NM_000284.4	c.*614G>T		3_prime_UTR_variant	11/11	ENST00000422285.7
MAP3K15	NM_001001671.4	c.*482C>A		3_prime_UTR_variant	29/29	ENST00000338883.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAP3K15	ENST00000338883.9	c.*482C>A		3_prime_UTR_variant	29/29	5	NM_001001671.4	P1
PDHA1	ENST00000422285.7	c.*614G>T		3_prime_UTR_variant	11/11	1	NM_000284.4	P1

Frequencies

GnomAD3 genomes AF: 0.0629 AC: 7059 AN: 112297 Hom.: 312 Cov.: 24 AF XY: 0.0613 AC XY: 2115 AN XY: 34507

Gnomad AFR AF: 0.153

Gnomad AMI AF: 0.115

Gnomad AMR AF: 0.0297

Gnomad ASJ AF: 0.0703

Gnomad EAS AF: 0.00443

Gnomad SAS AF: 0.125

Gnomad FIN AF: 0.0189

Gnomad MID AF: 0.113

Gnomad NFE AF: 0.0221

Gnomad OTH AF: 0.0556

GnomAD4 exome AF: 0.0288 AC: 648 AN: 22521 Hom.: 14 Cov.: 0 AF XY: 0.0378 AC XY: 178 AN XY: 4703

Gnomad4 AFR exome AF: 0.0815

Gnomad4 AMR exome AF: 0.0214

Gnomad4 ASJ exome AF: 0.0476

Gnomad4 EAS exome AF: 0.00148

Gnomad4 SAS exome AF: 0.108

Gnomad4 FIN exome AF: 0.0253

Gnomad4 NFE exome AF: 0.0183

Gnomad4 OTH exome AF: 0.0292

GnomAD4 genome AF: 0.0629 AC: 7067 AN: 112351 Hom.: 311 Cov.: 24 AF XY: 0.0614 AC XY: 2124 AN XY: 34571

Gnomad4 AFR AF: 0.153

Gnomad4 AMR AF: 0.0297

Gnomad4 ASJ AF: 0.0703

Gnomad4 EAS AF: 0.00444

Gnomad4 SAS AF: 0.126

Gnomad4 FIN AF: 0.0189

Gnomad4 NFE AF: 0.0221

Gnomad4 OTH AF: 0.0549

Alfa AF: 0.0304 Hom.: 988

Bravo AF: 0.0676

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 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. -

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	0.58
DANN	Benign	0.32

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: rs5955761; hg19: chrX-19378385;