Genetic Variant MAP3K14:p.His529Gln (chr17-45273573-G-C) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_003954.5(MAP3K14):c.1587C>G(p.His529Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,136 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/17 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. H529H) 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

Not reported in ClinVar

Conservation

PhyloP100: -2.03

Publications

0 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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.029353708).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
MAP3K14	NM_003954.5 link	c.1587C>G	p.His529Gln	missense_variant	Exon 9 of 16	ENST00000344686.8	NP_003945.2
MAP3K14	XM_047436997.1 link	c.1587C>G	p.His529Gln	missense_variant	Exon 9 of 15		XP_047292953.1
MAP3K14	XM_047436998.1 link	c.1587C>G	p.His529Gln	missense_variant	Exon 10 of 16		XP_047292954.1
MAP3K14	XM_011525441.3 link	c.1587C>G	p.His529Gln	missense_variant	Exon 10 of 17		XP_011523743.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAP3K14	ENST00000344686.8 link	c.1587C>G	p.His529Gln	missense_variant	Exon 9 of 16	1	NM_003954.5	ENSP00000478552.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461136

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726792

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33476

American (AMR)

AF:

0.00

AC:

AN:

44652

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26110

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.00

AC:

AN:

86118

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53274

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

9.00e-7

AC:

AN:

1111682

Other (OTH)

AF:

0.00

AC:

AN:

60360

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.097

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.57

CADD

Benign

0.040

(source)

DANN

Benign

0.89

DEOGEN2

Benign

0.13

T;T;T

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.059

LIST_S2

Benign

0.0

.;T;.

MetaRNN

Benign

0.029

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.61

N;N;N

PhyloP100

-2.0

PrimateAI

Benign

0.23

PROVEAN

Benign

0.0

.;.;.

REVEL

Benign

0.0

Sift

Pathogenic

0.0

.;.;.

Sift4G

Pathogenic

0.0

.;T;T

Vest4

0.0

ClinPred

0.26

GERP RS

-11

Varity_R

0.11

gMVP

0.57

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over