X-19360785-C-A

Variant names:

• chrX-19360785-C-A
• rs145675672
• NM_001001671.4:c.3906G>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.3906G>T​(p.Arg1302Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000912 in 1,095,898 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. 16/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1302K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: MAP3K15 NM_001001671.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.170
• Publications: 0 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 (MetaRNN=0.053584903).

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.3906G>T	p.Arg1302Ser	missense	Exon 29 of 29	NP_001001671.3	Q6ZN16-1
	PDHA1	NM_000284.4	MANE Select	c.*1132C>A		3_prime_UTR	Exon 11 of 11	NP_000275.1	P08559-1
	PDHA1	NM_001173454.2		c.*1132C>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.3906G>T	p.Arg1302Ser	missense	Exon 29 of 29	ENSP00000345629.4	Q6ZN16-1
	PDHA1	ENST00000422285.7	TSL:1 MANE Select	c.*1132C>A		3_prime_UTR	Exon 11 of 11	ENSP00000394382.2	P08559-1
	MAP3K15	ENST00000927253.1		c.3939G>T	p.Arg1313Ser	missense	Exon 30 of 30	ENSP00000597312.1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome AF: 9.12e-7 AC: 1 AN: 1095898 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 361404

African (AFR) AF: 0.00 AC: 0 AN: 26235

American (AMR) AF: 0.00 AC: 0 AN: 34724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19297

East Asian (EAS) AF: 0.00 AC: 0 AN: 30152

South Asian (SAS) AF: 0.00 AC: 0 AN: 53763

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40441

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4125

European-Non Finnish (NFE) AF: 0.00000119 AC: 1 AN: 841159

Other (OTH) AF: 0.00 AC: 0 AN: 46002

GnomAD4 genome Cov.: 24

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	14
DANN	Benign	0.96
DEOGEN2	Benign	0.0093	T
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.41	T
M_CAP	Benign	0.0040	T
MetaRNN	Benign	0.054	T
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	1.8	L
PhyloP100		-0.17
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.16
Sift	Benign	0.25	T
Sift4G	Benign	0.55	T
Polyphen		0.085	B
Vest4		0.061
MutPred		0.24		Loss of MoRF binding (P = 0.0273)
MVP		0.86
MPC		0.056
ClinPred		0.16	T
GERP RS		-1.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.56
gMVP		0.14
Mutation Taster		=99/1	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: rs145675672; hg19: chrX-19378903;