17-63667013-A-G

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_002401.5(MAP3K3):ā€‹c.455A>Gā€‹(p.Asn152Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000936 in 1,612,644 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: š‘“ 0.00019 ( 0 hom., cov: 32)
Exomes š‘“: 0.000084 ( 1 hom. )

Consequence

MAP3K3
NM_002401.5 missense

Scores

3
16

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.43
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 Benign. Variant got -8 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.02724588).
BS2
High AC in GnomAd4 at 29 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
MAP3K3NM_002401.5 linkuse as main transcriptc.455A>G p.Asn152Ser missense_variant 6/16 ENST00000361733.8 NP_002392.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
MAP3K3ENST00000361733.8 linkuse as main transcriptc.455A>G p.Asn152Ser missense_variant 6/161 NM_002401.5 ENSP00000354485 A1Q99759-1

Frequencies

GnomAD3 genomes
AF:
0.000191
AC:
29
AN:
152122
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000242
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00164
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:
0.0000441
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000108
AC:
27
AN:
249178
Hom.:
0
AF XY:
0.000119
AC XY:
16
AN XY:
134902
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000503
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:
0.0000794
Gnomad OTH exome
AF:
0.000166
GnomAD4 exome
AF:
0.0000835
AC:
122
AN:
1460404
Hom.:
1
Cov.:
31
AF XY:
0.0000840
AC XY:
61
AN XY:
726614
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.000497
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:
0.0000765
Gnomad4 OTH exome
AF:
0.000232
GnomAD4 genome
AF:
0.000190
AC:
29
AN:
152240
Hom.:
0
Cov.:
32
AF XY:
0.000255
AC XY:
19
AN XY:
74454
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.00163
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000441
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000899
Hom.:
1
Bravo
AF:
0.000276
ExAC
AF:
0.0000576
AC:
7
EpiCase
AF:
0.00
EpiControl
AF:
0.000119

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 submitterclinical testingAmbry GeneticsSep 30, 2021The c.548A>G (p.N183S) alteration is located in exon 7 (coding exon 7) of the MAP3K3 gene. This alteration results from a A to G substitution at nucleotide position 548, causing the asparagine (N) at amino acid position 183 to be replaced by a serine (S). 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
0.057
BayesDel_addAF
Benign
-0.42
T
BayesDel_noAF
Benign
-0.48
CADD
Benign
16
DANN
Benign
0.91
DEOGEN2
Benign
0.027
.;T;T;.;T
Eigen
Benign
-0.47
Eigen_PC
Benign
-0.22
FATHMM_MKL
Uncertain
0.78
D
LIST_S2
Uncertain
0.91
.;D;D;D;D
M_CAP
Benign
0.0057
T
MetaRNN
Benign
0.027
T;T;T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
-0.14
.;.;N;.;.
MutationTaster
Benign
0.98
D;D;D;D;D
PrimateAI
Uncertain
0.49
T
PROVEAN
Benign
-1.0
.;.;N;N;.
REVEL
Benign
0.082
Sift
Benign
0.28
.;.;T;T;.
Sift4G
Benign
0.89
T;T;T;T;T
Polyphen
0.0010
B;.;B;B;.
Vest4
0.20
MutPred
0.099
.;.;Gain of glycosylation at N152 (P = 0.0117);.;Gain of glycosylation at N152 (P = 0.0117);
MVP
0.47
MPC
0.076
ClinPred
0.047
T
GERP RS
5.1
Varity_R
0.064
gMVP
0.11

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

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

Other links and lift over

dbSNP: rs201709115; hg19: chr17-61744373; API