rs761104061

Variant summary

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

The NM_002401.5(MAP3K3):ā€‹c.421C>Gā€‹(p.Arg141Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000291 in 1,612,984 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: š‘“ 0.0000066 ( 0 hom., cov: 32)
Exomes š‘“: 0.000031 ( 0 hom. )

Consequence

MAP3K3
NM_002401.5 missense

Scores

2
7
10

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.72
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]

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 46 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MAP3K3NM_002401.5 linkc.421C>G p.Arg141Gly missense_variant Exon 6 of 16 ENST00000361733.8 NP_002392.2 Q99759-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
MAP3K3ENST00000361733.8 linkc.421C>G p.Arg141Gly missense_variant Exon 6 of 16 1 NM_002401.5 ENSP00000354485.4 Q99759-1

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152134
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
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
GnomAD4 exome
AF:
0.0000315
AC:
46
AN:
1460850
Hom.:
0
Cov.:
31
AF XY:
0.0000330
AC XY:
24
AN XY:
726806
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000405
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152134
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74322
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.45
BayesDel_addAF
Pathogenic
0.27
D
BayesDel_noAF
Pathogenic
0.15
CADD
Benign
22
DANN
Uncertain
1.0
DEOGEN2
Benign
0.025
.;T;T;.;T
Eigen
Benign
-0.15
Eigen_PC
Benign
0.011
FATHMM_MKL
Uncertain
0.87
D
LIST_S2
Uncertain
0.95
.;D;D;D;D
M_CAP
Benign
0.033
D
MetaRNN
Uncertain
0.63
D;D;D;D;D
MetaSVM
Benign
-0.84
T
MutationAssessor
Benign
1.8
.;.;L;.;.
PrimateAI
Uncertain
0.56
T
PROVEAN
Benign
-0.79
.;.;N;N;.
REVEL
Uncertain
0.29
Sift
Benign
0.28
.;.;T;T;.
Sift4G
Benign
0.15
T;T;T;T;T
Polyphen
0.23
B;.;B;B;.
Vest4
0.77
MutPred
0.17
.;.;Loss of MoRF binding (P = 0.0143);.;Loss of MoRF binding (P = 0.0143);
MVP
0.95
MPC
0.12
ClinPred
0.52
D
GERP RS
4.1
Varity_R
0.30
gMVP
0.59

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.10
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.

Other links and lift over

dbSNP: rs761104061; hg19: chr17-61744339; API