NM_003954.5:c.2290A>G

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_003954.5(MAP3K14):c.2290A>G(p.Thr764Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0029 in 1,606,984 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T764I) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0020 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0030 ( 6 hom. )

Consequence

MAP3K14
NM_003954.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 0.701

Publications

5 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 links:

MAP3K14-AS1 (HGNC:44359): (MAP3K14 antisense RNA 1)

MAP3K14-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.007188499).

BP6

Variant 17-45267442-T-C is Benign according to our data. Variant chr17-45267442-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 478059. Variant chr17-45267442-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 478059. Variant chr17-45267442-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 478059. Variant chr17-45267442-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 478059. Variant chr17-45267442-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 478059. Variant chr17-45267442-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 478059. Variant chr17-45267442-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 478059. Variant chr17-45267442-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 478059. Variant chr17-45267442-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 478059. Variant chr17-45267442-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 478059. Variant chr17-45267442-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 478059.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAP3K14	NM_003954.5 link	c.2290A>G	p.Thr764Ala	missense_variant	Exon 12 of 16	ENST00000344686.8	NP_003945.2	Q99558Q68D39

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAP3K14	ENST00000344686.8 link	c.2290A>G	p.Thr764Ala	missense_variant	Exon 12 of 16	1	NM_003954.5	ENSP00000478552.1		Q99558

Frequencies

GnomAD3 genomes

AF:

0.00198

AC:

301

AN:

152216

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000675

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00144

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00350

Gnomad OTH

AF:

0.00143

GnomAD2 exomes

AF:

0.00188

AC:

442

AN:

235416

AF XY:

0.00177

show subpopulations

Gnomad AFR exome

AF:

0.000856

Gnomad AMR exome

AF:

0.000579

Gnomad ASJ exome

AF:

0.000104

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00106

Gnomad NFE exome

AF:

0.00356

Gnomad OTH exome

AF:

0.00122

GnomAD4 exome

AF:

0.00299

AC:

4352

AN:

1454650

Hom.:

Cov.:

AF XY:

0.00282

AC XY:

2037

AN XY:

723094

show subpopulations

African (AFR)

AF:

0.000630

AC:

AN:

33344

American (AMR)

AF:

0.000485

AC:

AN:

43308

Ashkenazi Jewish (ASJ)

AF:

0.000155

AC:

AN:

25886

East Asian (EAS)

AF:

0.00

AC:

AN:

39536

South Asian (SAS)

AF:

0.000106

AC:

AN:

85120

European-Finnish (FIN)

AF:

0.000905

AC:

AN:

53050

Middle Eastern (MID)

AF:

0.000354

AC:

AN:

5642

European-Non Finnish (NFE)

AF:

0.00375

AC:

4153

AN:

1108694

Other (OTH)

AF:

0.00156

AC:

AN:

60070

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

254

507

761

1014

1268

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

164

328

492

656

820

<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:

0.00198

AC:

301

AN:

152334

Hom.:

Cov.:

AF XY:

0.00181

AC XY:

135

AN XY:

74510

show subpopulations

African (AFR)

AF:

0.000673

AC:

AN:

41582

American (AMR)

AF:

0.00144

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.000942

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00350

AC:

238

AN:

68014

Other (OTH)

AF:

0.00142

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

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:

0.00220

Hom.:

Bravo

AF:

0.00178

TwinsUK

AF:

0.00324

AC:

ALSPAC

AF:

0.00363

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00193

AC:

ExAC

AF:

0.00167

AC:

202

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Apr 13, 2020

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The MAP3K14 c.2290A>G; p.Thr764Ala variant (rs56302559), to our knowledge, is not reported in the medical literature but is reported as likely benign in ClinVar (Variation ID: 478059). This variant is found in the general population with an overall allele frequency of 0.19% (495/266794 alleles) in the Genome Aggregation Database. The threonine at codon 764 is highly conserved, but computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. Due to limited information, the clinical significance of the p.Thr764Ala variant is uncertain at this time. -

NIK deficiency

Benign:1

Jan 31, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.065

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.38

CADD

Benign

(source)

DANN

Benign

0.85

DEOGEN2

Benign

0.29

T;T;T

Eigen

Benign

-0.74

Eigen_PC

Benign

-0.66

FATHMM_MKL

Benign

0.56

LIST_S2

Benign

0.53

.;T;.

MetaRNN

Benign

0.0072

T;T;T

MetaSVM

Benign

-0.93

MutationAssessor

Benign

1.7

L;L;L

PhyloP100

0.70

PrimateAI

Benign

0.35

REVEL

Benign

0.052

Sift4G

Benign

0.45

.;T;T

Polyphen

0.058

B;B;B

Vest4

0.12, 0.12

MVP

0.13

ClinPred

0.0071

GERP RS

3.7

Varity_R

0.043

gMVP

0.22

Mutation Taster

=98/2

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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