rs15943

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

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. 11/19 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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 6.00

Publications

9 publications found

Variant links:

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]

MAP3K15 links:

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):

Leigh syndrome
Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
pyruvate dehydrogenase E1-alpha deficiency
Inheritance: XL, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet, Ambry Genetics
Leigh syndrome with leukodystrophy
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

PDHA1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId 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 link	c.3751C>G	p.Gln1251Glu	missense_variant	Exon 27 of 29	ENST00000338883.9	NP_001001671.3	Q6ZN16-1
PDHA1	NM_000284.4 link	c.*1869G>C		3_prime_UTR_variant	Exon 11 of 11	ENST00000422285.7	NP_000275.1	P08559-1A0A024RBX9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAP3K15	ENST00000338883.9 link	c.3751C>G	p.Gln1251Glu	missense_variant	Exon 27 of 29	5	NM_001001671.4	ENSP00000345629.4		Q6ZN16-1
PDHA1	ENST00000422285.7 link	c.*1869G>C		3_prime_UTR_variant	Exon 11 of 11	1	NM_000284.4	ENSP00000394382.2		P08559-1

Frequencies

GnomAD3 genomes

AF:

0.00432

AC:

486

AN:

112577

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.00369

AC:

675

AN:

183133

AF XY:

0.00414

show subpopulations

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 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.:

Cov.:

AF XY:

0.00555

AC XY:

2012

AN XY:

362617

show subpopulations

African (AFR)

AF:

0.000682

AC:

AN:

26385

American (AMR)

AF:

0.00207

AC:

AN:

35192

Ashkenazi Jewish (ASJ)

AF:

0.00542

AC:

105

AN:

19380

East Asian (EAS)

AF:

0.00

AC:

AN:

30197

South Asian (SAS)

AF:

0.00124

AC:

AN:

54078

European-Finnish (FIN)

AF:

0.00123

AC:

AN:

40488

Middle Eastern (MID)

AF:

0.00798

AC:

AN:

4136

European-Non Finnish (NFE)

AF:

0.00658

AC:

5539

AN:

841335

Other (OTH)

AF:

0.00463

AC:

213

AN:

46048

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

191

382

573

764

955

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

208

416

624

832

1040

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00430

AC:

484

AN:

112631

Hom.:

Cov.:

AF XY:

0.00385

AC XY:

134

AN XY:

34789

show subpopulations

African (AFR)

AF:

0.000965

AC:

AN:

31089

American (AMR)

AF:

0.00244

AC:

AN:

10638

Ashkenazi Jewish (ASJ)

AF:

0.00489

AC:

AN:

2659

East Asian (EAS)

AF:

0.00

AC:

AN:

3589

South Asian (SAS)

AF:

0.000362

AC:

AN:

2760

European-Finnish (FIN)

AF:

0.000490

AC:

AN:

6125

Middle Eastern (MID)

AF:

0.0184

AC:

AN:

217

European-Non Finnish (NFE)

AF:

0.00746

AC:

398

AN:

53334

Other (OTH)

AF:

0.00587

AC:

AN:

1532

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

103

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00641

Hom.:

137

Bravo

AF:

0.00414

TwinsUK

AF:

0.00566

AC:

ALSPAC

AF:

0.00346

AC:

ESP6500AA

AF:

0.00130

AC:

ESP6500EA

AF:

0.00773

AC:

ExAC

AF:

0.00377

AC:

458

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

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

- -

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

BayesDel_noAF

Benign

-0.22

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.016

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.87

MetaRNN

Benign

0.0083

MetaSVM

Uncertain

-0.029

MutationAssessor

Uncertain

2.8

PhyloP100

6.0

PrimateAI

Benign

0.37

PROVEAN

Benign

-1.5

REVEL

Uncertain

0.37

Sift

Benign

0.27

Sift4G

Benign

0.28

Polyphen

0.93

Vest4

0.089

MVP

0.66

MPC

0.094

ClinPred

0.042

GERP RS

5.0

Varity_R

0.41

gMVP

0.34

Mutation Taster

=95/5

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over