chr17-45264683-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2PP2BP4_Moderate

The NM_003954.5(MAP3K14):​c.2797G>A​(p.Ala933Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000187 in 1,601,400 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/15 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

MAP3K14
NM_003954.5 missense

Scores

1
14

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.379
Variant links:
Genes affected
MAP3K14 (HGNC:6853): (mitogen-activated protein kinase kinase kinase 14) This gene encodes mitogen-activated protein kinase kinase kinase 14, which is a serine/threonine protein-kinase. This kinase binds to TRAF2 and stimulates NF-kappaB activity. It shares sequence similarity with several other MAPKK kinases. It participates in an NF-kappaB-inducing signalling cascade common to receptors of the tumour-necrosis/nerve-growth factor (TNF/NGF) family and to the interleukin-1 type-I receptor. [provided by RefSeq, Jul 2008]
MAP3K14-AS1 (HGNC:44359): (MAP3K14 antisense RNA 1)

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), MAP3K14. . Trascript score misZ 4.5031 (greater than threshold 3.09). GenCC has associacion of gene with NIK deficiency.
BP4
Computational evidence support a benign effect (MetaRNN=0.07228407).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
MAP3K14NM_003954.5 linkuse as main transcriptc.2797G>A p.Ala933Thr missense_variant 16/16 ENST00000344686.8
MAP3K14-AS1NR_110325.1 linkuse as main transcriptn.260-2430C>T intron_variant, non_coding_transcript_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
MAP3K14ENST00000344686.8 linkuse as main transcriptc.2797G>A p.Ala933Thr missense_variant 16/161 NM_003954.5 P1
MAP3K14-AS1ENST00000657572.1 linkuse as main transcriptn.170-2430C>T intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes
AF:
0.0000263
AC:
4
AN:
152204
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000654
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000133
AC:
3
AN:
225722
Hom.:
0
AF XY:
0.00000815
AC XY:
1
AN XY:
122668
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
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:
0.0000296
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000179
AC:
26
AN:
1449196
Hom.:
0
Cov.:
30
AF XY:
0.0000167
AC XY:
12
AN XY:
719802
show subpopulations
Gnomad4 AFR exome
AF:
0.0000301
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000357
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000190
Gnomad4 OTH exome
AF:
0.0000167
GnomAD4 genome
AF:
0.0000263
AC:
4
AN:
152204
Hom.:
0
Cov.:
33
AF XY:
0.0000404
AC XY:
3
AN XY:
74342
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.0000654
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000254
Hom.:
0
Bravo
AF:
0.0000113
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000117
AC:
1
ExAC
AF:
0.00000826
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

NIK deficiency Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingInvitaeJun 13, 2022This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 933 of the MAP3K14 protein (p.Ala933Thr). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with MAP3K14-related conditions. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.074
BayesDel_addAF
Benign
0.00037
T
BayesDel_noAF
Benign
-0.24
CADD
Benign
17
DANN
Uncertain
0.99
DEOGEN2
Benign
0.34
T;T;T
Eigen
Benign
-0.57
Eigen_PC
Benign
-0.48
FATHMM_MKL
Benign
0.25
N
LIST_S2
Benign
0.72
.;T;.
MetaRNN
Benign
0.072
T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
0.34
N;N;N
PrimateAI
Benign
0.43
T
REVEL
Benign
0.086
Sift4G
Benign
0.099
.;T;T
Polyphen
0.0020
B;B;B
Vest4
0.071, 0.072
MVP
0.14
ClinPred
0.12
T
GERP RS
1.1
Varity_R
0.058
gMVP
0.35

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: rs375320125; hg19: chr17-43342050; API