NM_001001671.4:c.3751C>G

Variant names:

• chrX-19361522-G-C
• rs15943
• NM_001001671.4:c.3751C>G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001001671.4(MAP3K15):​c.3751C>G​(p.Gln1251Glu) variant causes a missense change. The variant allele was found at a frequency of 0.00544 in 1,209,870 control chromosomes in the GnomAD database, including 15 homozygotes. There are 2,146 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 11/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0043 (0 hom., 134 hem., cov: 24)
  • Exomes 𝑓: 0.0056 (15 hom. 2012 hem.)
• Consequence: MAP3K15 NM_001001671.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 6.00

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]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008258253).
• BP6: Variant X-19361522-G-C is Benign according to our data. Variant chrX-19361522-G-C is described in ClinVar as [Benign]. Clinvar id is 376916.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Hemizygotes in GnomAd4 at 134 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAP3K15	NM_001001671.4	c.3751C>G	p.Gln1251Glu	missense_variant	Exon 27 of 29	ENST00000338883.9	NP_001001671.3
PDHA1	NM_000284.4	c.*1869G>C		3_prime_UTR_variant	Exon 11 of 11	ENST00000422285.7	NP_000275.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAP3K15	ENST00000338883.9	c.3751C>G	p.Gln1251Glu	missense_variant	Exon 27 of 29	5	NM_001001671.4	ENSP00000345629.4
PDHA1	ENST00000422285.7	c.*1869G>C		3_prime_UTR_variant	Exon 11 of 11	1	NM_000284.4	ENSP00000394382.2

Frequencies

GnomAD3 genomes AF: 0.00432 AC: 486 AN: 112577 Hom.: 0 Cov.: 24 AF XY: 0.00386 AC XY: 134 AN XY: 34725

Gnomad AFR AF: 0.000967

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00245

Gnomad ASJ AF: 0.00489

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000361

Gnomad FIN AF: 0.000490

Gnomad MID AF: 0.0252

Gnomad NFE AF: 0.00746

Gnomad OTH AF: 0.00595

GnomAD3 exomes AF: 0.00369 AC: 675 AN: 183133 Hom.: 2 AF XY: 0.00414 AC XY: 280 AN XY: 67589

Gnomad AFR exome AF: 0.00129

Gnomad AMR exome AF: 0.00168

Gnomad ASJ exome AF: 0.00602

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00116

Gnomad FIN exome AF: 0.000626

Gnomad NFE exome AF: 0.00627

Gnomad OTH exome AF: 0.00486

GnomAD4 exome AF: 0.00556 AC: 6098 AN: 1097239 Hom.: 15 Cov.: 29 AF XY: 0.00555 AC XY: 2012 AN XY: 362617

Gnomad4 AFR exome AF: 0.000682

Gnomad4 AMR exome AF: 0.00207

Gnomad4 ASJ exome AF: 0.00542

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00124

Gnomad4 FIN exome AF: 0.00123

Gnomad4 NFE exome AF: 0.00658

Gnomad4 OTH exome AF: 0.00463

GnomAD4 genome AF: 0.00430 AC: 484 AN: 112631 Hom.: 0 Cov.: 24 AF XY: 0.00385 AC XY: 134 AN XY: 34789

Gnomad4 AFR AF: 0.000965

Gnomad4 AMR AF: 0.00244

Gnomad4 ASJ AF: 0.00489

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000362

Gnomad4 FIN AF: 0.000490

Gnomad4 NFE AF: 0.00746

Gnomad4 OTH AF: 0.00587

Alfa AF: 0.00641 Hom.: 137

Bravo AF: 0.00414

TwinsUK AF: 0.00566 AC: 21

ALSPAC AF: 0.00346 AC: 10

ESP6500AA AF: 0.00130 AC: 5

ESP6500EA AF: 0.00773 AC: 52

ExAC AF: 0.00377 AC: 458

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jul 12, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Pyruvate dehydrogenase E1-alpha deficiency Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

MAP3K15-related disorder Benign:1

Apr 25, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	18
DANN	Benign	0.97
DEOGEN2	Benign	0.016	T
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.87	D
MetaRNN	Benign	0.0083	T
MetaSVM	Uncertain	-0.029	T
MutationAssessor	Uncertain	2.8	M
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.5	N
REVEL	Uncertain	0.37
Sift	Benign	0.27	T
Sift4G	Benign	0.28	T
Polyphen		0.93	P
Vest4		0.089
MVP		0.66
MPC		0.094
ClinPred		0.042	T
GERP RS		5.0
Varity_R		0.41
gMVP		0.34

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: rs15943; hg19: chrX-19379640;