rs1042452

Variant names:

• chrX-19360381-C-A
• rs1042452
• NM_001001671.4:c.*368G>T

Your query was ambiguous. Multiple possible variants found:

• chrX-19360381-C-A
• chrX-19360381-C-T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001001671.4(MAP3K15):​c.*368G>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 0.0000201 in 49,825 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.000020 (0 hom. 0 hem.)
• Consequence: MAP3K15 NM_001001671.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0340
• Publications: 2 publications found

Genes affected

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]

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]

PDHA1 Gene-Disease associations (from GenCC):

• pyruvate dehydrogenase E1-alpha deficiency

  Inheritance: AR, XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Genomics England PanelApp, G2P, Orphanet, Labcorp Genetics (formerly Invitae)
• Leigh syndrome

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
• Leigh syndrome with leukodystrophy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001001671.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAP3K15	NM_001001671.4	MANE Select	c.*368G>T		3_prime_UTR	Exon 29 of 29	NP_001001671.3	Q6ZN16-1
	PDHA1	NM_000284.4	MANE Select	c.*728C>A		3_prime_UTR	Exon 11 of 11	NP_000275.1	P08559-1
	PDHA1	NM_001173454.2		c.*728C>A		3_prime_UTR	Exon 12 of 12	NP_001166925.1	P08559-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAP3K15	ENST00000338883.9	TSL:5 MANE Select	c.*368G>T		3_prime_UTR	Exon 29 of 29	ENSP00000345629.4	Q6ZN16-1
	PDHA1	ENST00000422285.7	TSL:1 MANE Select	c.*728C>A		3_prime_UTR	Exon 11 of 11	ENSP00000394382.2	P08559-1
	MAP3K15	ENST00000947404.1		c.*368G>T		3_prime_UTR	Exon 29 of 29	ENSP00000617463.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.0000201 AC: 1 AN: 49825 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 11149

African (AFR) AF: 0.00 AC: 0 AN: 503

American (AMR) AF: 0.00 AC: 0 AN: 1844

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1125

East Asian (EAS) AF: 0.00 AC: 0 AN: 1131

South Asian (SAS) AF: 0.00 AC: 0 AN: 5483

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 3054

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 194

European-Non Finnish (NFE) AF: 0.0000298 AC: 1 AN: 33588

Other (OTH) AF: 0.00 AC: 0 AN: 2903

GnomAD4 genome Cov.: 23

Alfa AF: 0.0000675 Hom.: 1147

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	2.4
DANN	Benign	0.82
PhyloP100		0.034
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs1042452; hg19: chrX-19378499;