X-19360085-C-T

Position:

• chrX-19360085-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP6 BS2

The NM_001001671.4(MAP3K15):​c.*664G>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 0.000665 in 169,949 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 44 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00068 (0 hom., 28 hem., cov: 23)
  • Exomes 𝑓: 0.00063 (0 hom. 16 hem.)
• Consequence: MAP3K15 NM_001001671.4 3_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: -0.0820

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 Likely_benign. Variant got -5 ACMG points.

• BP6: Variant X-19360085-C-T is Benign according to our data. Variant chrX-19360085-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 913342.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.
• BS2: High Hemizygotes in GnomAd4 at 28 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PDHA1	NM_000284.4	c.*432C>T		3_prime_UTR_variant	11/11	ENST00000422285.7
MAP3K15	NM_001001671.4	c.*664G>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.*664G>A		3_prime_UTR_variant	29/29	5	NM_001001671.4	P1
PDHA1	ENST00000422285.7	c.*432C>T		3_prime_UTR_variant	11/11	1	NM_000284.4	P1

Frequencies

GnomAD3 genomes AF: 0.000683 AC: 75 AN: 109886 Hom.: 0 Cov.: 23 AF XY: 0.000865 AC XY: 28 AN XY: 32352

Gnomad AFR AF: 0.000171

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00231

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00855

Gnomad NFE AF: 0.000736

Gnomad OTH AF: 0.00341

GnomAD4 exome AF: 0.000633 AC: 38 AN: 60018 Hom.: 0 Cov.: 0 AF XY: 0.00141 AC XY: 16 AN XY: 11362

Gnomad4 AFR exome AF: 0.000607

Gnomad4 AMR exome AF: 0.000721

Gnomad4 ASJ exome AF: 0.00129

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000641

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000645

Gnomad4 OTH exome AF: 0.000599

GnomAD4 genome AF: 0.000682 AC: 75 AN: 109931 Hom.: 0 Cov.: 23 AF XY: 0.000864 AC XY: 28 AN XY: 32407

Gnomad4 AFR AF: 0.000171

Gnomad4 AMR AF: 0.00231

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000736

Gnomad4 OTH AF: 0.00337

Alfa AF: 0.000925 Hom.: 3

Bravo AF: 0.000589

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2022	MAP3K15: BS2; PDHA1: BS2 -

Pyruvate dehydrogenase E1-alpha deficiency Uncertain:1

Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	11
DANN	Benign	0.61

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.21		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.21		Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs754719295; hg19: chrX-19378203;