17-63689571-G-A

Position:

chr17-63689571-G-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_002401.5(MAP3K3):c.899G>A(p.Arg300His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000316 in 1,613,594 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000032 ( 0 hom. )

Consequence

MAP3K3
NM_002401.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.89

Variant links:

Genes affected

MAP3K3 (HGNC:6855): (mitogen-activated protein kinase kinase kinase 3) This gene product is a 626-amino acid polypeptide that is 96.5% identical to mouse Mekk3. Its catalytic domain is closely related to those of several other kinases, including mouse Mekk2, tobacco NPK, and yeast Ste11. Northern blot analysis revealed a 4.6-kb transcript that appears to be ubiquitously expressed. This protein directly regulates the stress-activated protein kinase (SAPK) and extracellular signal-regulated protein kinase (ERK) pathways by activating SEK and MEK1/2 respectively; it does not regulate the p38 pathway. In cotransfection assays, it enhanced transcription from a nuclear factor kappa-B (NFKB)-dependent reporter gene, consistent with a role in the SAPK pathway. Alternatively spliced transcript variants encoding distinct isoforms have been observed. [provided by RefSeq, Jul 2008]

MAP3K3 links:

LOC101927898 (HGNC:):

LOC101927898 links:

STRADA (HGNC:30172): (STE20 related adaptor alpha) The protein encoded by this gene contains a STE20-like kinase domain, but lacks several residues that are critical for catalytic activity, so it is termed a 'pseudokinase'. The protein forms a heterotrimeric complex with serine/threonine kinase 11 (STK11, also known as LKB1) and the scaffolding protein calcium binding protein 39 (CAB39, also known as MO25). The protein activates STK11 leading to the phosphorylation of both proteins and excluding STK11 from the nucleus. The protein is necessary for STK11-induced G1 cell cycle arrest. A mutation in this gene has been shown to result in polyhydramnios, megalencephaly, and symptomatic epilepsy (PMSE) syndrome. Multiple transcript variants encoding different isoforms have been found for this gene. Additional transcript variants have been described but their full-length nature is not known. [provided by RefSeq, Sep 2009]

STRADA links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BS2

High AC in GnomAdExome4 at 47 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MAP3K3	NM_002401.5 linkuse as main transcript	c.899G>A	p.Arg300His	missense_variant	11/16	ENST00000361733.8	NP_002392.2
LOC101927898	XR_243740.4 linkuse as main transcript	n.526-396C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAP3K3	ENST00000361733.8 linkuse as main transcript	c.899G>A	p.Arg300His	missense_variant	11/16	1	NM_002401.5	ENSP00000354485	A1	Q99759-1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000200

AC:

AN:

249872

Hom.:

AF XY:

0.00000740

AC XY:

AN XY:

135164

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000354

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000322

AC:

AN:

1461292

Hom.:

Cov.:

AF XY:

0.0000261

AC XY:

AN XY:

726892

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000369

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152302

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74472

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000128

Hom.:

Bravo

AF:

0.0000227

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.0000594

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 05, 2022

The c.992G>A (p.R331H) alteration is located in exon 12 (coding exon 12) of the MAP3K3 gene. This alteration results from a G to A substitution at nucleotide position 992, causing the arginine (R) at amino acid position 331 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Uncertain

0.041

BayesDel_noAF

Uncertain

-0.050

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.036

.;T;T;.;T

Eigen

Pathogenic

0.76

Eigen_PC

Pathogenic

0.74

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.98

.;D;D;D;D

M_CAP

Benign

0.025

MetaRNN

Uncertain

0.68

D;D;D;D;D

MetaSVM

Benign

-0.43

MutationAssessor

Uncertain

2.5

.;.;M;.;.

MutationTaster

Benign

1.0

D;D;D;D;D

PrimateAI

Pathogenic

0.84

PROVEAN

Benign

-1.7

.;.;N;N;.

REVEL

Uncertain

0.33

Sift

Benign

0.10

.;.;T;T;.

Sift4G

Benign

0.38

T;T;T;T;T

Polyphen

1.0

D;.;D;D;.

Vest4

0.74

MVP

0.71

MPC

1.9

ClinPred

0.68

GERP RS

4.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.16

gMVP

0.67

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over