rs148344770

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBP6_Very_Strong

The NM_003954.5(MAP3K14):c.774C>G(p.Phe258Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000657 in 1,613,360 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 10/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00038 ( 1 hom. )

Consequence

MAP3K14
NM_003954.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 1.31

Publications

1 publications found

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 Gene-Disease associations (from GenCC):

NIK deficiency
Inheritance: AR Classification: MODERATE, SUPPORTIVE Submitted by: Orphanet, ClinGen

MAP3K14 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0067031085).

BP6

Variant 17-45286809-G-C is Benign according to our data. Variant chr17-45286809-G-C is described in ClinVar as Benign. ClinVar VariationId is 544331.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAP3K14	NM_003954.5 link	c.774C>G	p.Phe258Leu	missense_variant	Exon 5 of 16	ENST00000344686.8	NP_003945.2	Q99558Q68D39
MAP3K14	XM_047436997.1 link	c.774C>G	p.Phe258Leu	missense_variant	Exon 5 of 15		XP_047292953.1
MAP3K14	XM_047436998.1 link	c.774C>G	p.Phe258Leu	missense_variant	Exon 6 of 16		XP_047292954.1
MAP3K14	XM_011525441.3 link	c.774C>G	p.Phe258Leu	missense_variant	Exon 6 of 17		XP_011523743.1	Q99558

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MAP3K14	ENST00000344686.8 link	c.774C>G	p.Phe258Leu	missense_variant	Exon 5 of 16	1	NM_003954.5	ENSP00000478552.1	Q99558
MAP3K14	ENST00000376926.8 link	c.774C>G	p.Phe258Leu	missense_variant	Exon 4 of 15	1		ENSP00000482657.1	Q99558
MAP3K14	ENST00000617331.3 link	c.774C>G	p.Phe258Leu	missense_variant	Exon 6 of 17	5		ENSP00000480974.3	Q99558A0A087WXF1

Frequencies

GnomAD3 genomes

AF:

0.00330

AC:

502

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0111

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00144

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:

0.000176

Gnomad OTH

AF:

0.00334

GnomAD2 exomes

AF:

0.000804

AC:

198

AN:

246240

AF XY:

0.000523

show subpopulations

Gnomad AFR exome

AF:

0.0109

Gnomad AMR exome

AF:

0.000641

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000988

Gnomad OTH exome

AF:

0.000167

GnomAD4 exome

AF:

0.000381

AC:

557

AN:

1461044

Hom.:

Cov.:

AF XY:

0.000332

AC XY:

241

AN XY:

726744

show subpopulations

African (AFR)

AF:

0.0118

AC:

395

AN:

33472

American (AMR)

AF:

0.000717

AC:

AN:

44610

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26110

East Asian (EAS)

AF:

0.00

AC:

AN:

39674

South Asian (SAS)

AF:

0.0000348

AC:

AN:

86140

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53324

Middle Eastern (MID)

AF:

0.00260

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000504

AC:

AN:

1111588

Other (OTH)

AF:

0.000928

AC:

AN:

60358

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.512

Heterozygous variant carriers

141

188

235

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00330

AC:

503

AN:

152316

Hom.:

Cov.:

AF XY:

0.00306

AC XY:

228

AN XY:

74482

show subpopulations

African (AFR)

AF:

0.0111

AC:

462

AN:

41572

American (AMR)

AF:

0.00144

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.000176

AC:

AN:

68026

Other (OTH)

AF:

0.00331

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.513

Heterozygous variant carriers

106

132

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000960

Hom.:

Bravo

AF:

0.00389

ESP6500AA

AF:

0.0111

AC:

ESP6500EA

AF:

0.000122

AC:

ExAC

AF:

0.000976

AC:

118

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

NIK deficiency

Benign:1

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.75

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.60

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.26

T;T;T

Eigen

Benign

-0.47

Eigen_PC

Benign

-0.36

FATHMM_MKL

Uncertain

0.79

LIST_S2

Benign

0.60

.;T;.

MetaRNN

Benign

0.0067

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.90

L;L;L

PhyloP100

1.3

PrimateAI

Uncertain

0.59

REVEL

Benign

0.063

Sift4G

Benign

0.11

.;T;T

Polyphen

0.0010

B;B;B

Vest4

0.30, 0.30

MutPred

0.21

Gain of glycosylation at P254 (P = 0.0893);Gain of glycosylation at P254 (P = 0.0893);Gain of glycosylation at P254 (P = 0.0893);

MVP

0.16

ClinPred

0.035

GERP RS

1.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.8

Varity_R

0.24

gMVP

0.12

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over