rs747466210

Variant summary

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

The NM_003954.5(MAP3K14):c.820C>T(p.Pro274Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,172 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 (★). Synonymous variant affecting the same amino acid position (i.e. P274P) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

MAP3K14
NM_003954.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.17

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 links:

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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 where missense usually causes diseases, MAP3K14

BP4

Computational evidence support a benign effect (MetaRNN=0.12510368).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
MAP3K14	NM_003954.5 linkuse as main transcript	c.820C>T	p.Pro274Ser	missense_variant	5/16	ENST00000344686.8
MAP3K14	XM_047436997.1 linkuse as main transcript	c.820C>T	p.Pro274Ser	missense_variant	5/15
MAP3K14	XM_047436998.1 linkuse as main transcript	c.820C>T	p.Pro274Ser	missense_variant	6/16
MAP3K14	XM_011525441.3 linkuse as main transcript	c.820C>T	p.Pro274Ser	missense_variant	6/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
MAP3K14	ENST00000344686.8 linkuse as main transcript	c.820C>T	p.Pro274Ser	missense_variant	5/16	1	NM_003954.5	P1
MAP3K14	ENST00000376926.8 linkuse as main transcript	c.820C>T	p.Pro274Ser	missense_variant	4/15	1		P1
MAP3K14	ENST00000617331.3 linkuse as main transcript	c.820C>T	p.Pro274Ser	missense_variant	6/17	5		P1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000407

AC:

AN:

245400

Hom.:

AF XY:

0.00000751

AC XY:

AN XY:

133136

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:

0.0000331

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460172

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726178

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:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000827

AC:

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 submitter

clinical testing

Invitae

Nov 06, 2018

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. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C15"). This variant has not been reported in the literature in individuals with MAP3K14-related disease. This variant is present in population databases (rs747466210, ExAC 0.007%). This sequence change replaces proline with serine at codon 274 of the MAP3K14 protein (p.Pro274Ser). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and serine. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.093

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.46

Cadd

Benign

Dann

Uncertain

1.0

DEOGEN2

Benign

0.21

T;T;T

Eigen

Benign

-0.073

Eigen_PC

Benign

0.055

FATHMM_MKL

Uncertain

0.85

MetaRNN

Benign

0.13

T;T;T

MetaSVM

Benign

-0.92

MutationAssessor

Benign

0.90

L;L;L

PrimateAI

Benign

0.36

Polyphen

0.44

B;B;B

Vest4

0.32, 0.30

MutPred

0.30

Loss of glycosylation at K276 (P = 0.175);Loss of glycosylation at K276 (P = 0.175);Loss of glycosylation at K276 (P = 0.175);

MVP

0.44

ClinPred

0.58

GERP RS

3.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.21

gMVP

0.23

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.

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