rs15943

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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. 11/19 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 6.00
• Publications: 9 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: 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

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.3751C>G	p.Gln1251Glu	missense	Exon 27 of 29	NP_001001671.3	Q6ZN16-1
	PDHA1	NM_000284.4	MANE Select	c.*1869G>C		3_prime_UTR	Exon 11 of 11	NP_000275.1	P08559-1
	PDHA1	NM_001173454.2		c.*1869G>C		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.3751C>G	p.Gln1251Glu	missense	Exon 27 of 29	ENSP00000345629.4	Q6ZN16-1
	PDHA1	ENST00000422285.7	TSL:1 MANE Select	c.*1869G>C		3_prime_UTR	Exon 11 of 11	ENSP00000394382.2	P08559-1
	MAP3K15	ENST00000927253.1		c.3784C>G	p.Gln1262Glu	missense	Exon 28 of 30	ENSP00000597312.1

Frequencies

GnomAD3 genomes AF: 0.00432 AC: 486 AN: 112577 Hom.: 0 Cov.: 24

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

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.: 15 Cov.: 29 AF XY: 0.00555 AC XY: 2012 AN XY: 362617

African (AFR) AF: 0.000682 AC: 18 AN: 26385

American (AMR) AF: 0.00207 AC: 73 AN: 35192

Ashkenazi Jewish (ASJ) AF: 0.00542 AC: 105 AN: 19380

East Asian (EAS) AF: 0.00 AC: 0 AN: 30197

South Asian (SAS) AF: 0.00124 AC: 67 AN: 54078

European-Finnish (FIN) AF: 0.00123 AC: 50 AN: 40488

Middle Eastern (MID) AF: 0.00798 AC: 33 AN: 4136

European-Non Finnish (NFE) AF: 0.00658 AC: 5539 AN: 841335

Other (OTH) AF: 0.00463 AC: 213 AN: 46048

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

African (AFR) AF: 0.000965 AC: 30 AN: 31089

American (AMR) AF: 0.00244 AC: 26 AN: 10638

Ashkenazi Jewish (ASJ) AF: 0.00489 AC: 13 AN: 2659

East Asian (EAS) AF: 0.00 AC: 0 AN: 3589

South Asian (SAS) AF: 0.000362 AC: 1 AN: 2760

European-Finnish (FIN) AF: 0.000490 AC: 3 AN: 6125

Middle Eastern (MID) AF: 0.0184 AC: 4 AN: 217

European-Non Finnish (NFE) AF: 0.00746 AC: 398 AN: 53334

Other (OTH) AF: 0.00587 AC: 9 AN: 1532

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	MAP3K15-related disorder (1)
-	-	1	Pyruvate dehydrogenase E1-alpha deficiency (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		6.0
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
Mutation Taster		=95/5	polymorphism (auto)

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: rs15943; hg19: chrX-19379640;