17-45286703-T-G

Position:

chr17-45286703-T-G

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 1P and 12B. PP2BP4_StrongBP6_Very_Strong

The NM_003954.5(MAP3K14):c.880A>C(p.Lys294Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000199 in 1,610,040 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/15 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0012 ( 1 hom., cov: 32)

Exomes 𝑓: 0.000099 ( 1 hom. )

Consequence

MAP3K14
NM_003954.5 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.0800

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 Benign. Variant got -11 ACMG points.

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=0.0038543344).

BP6

Variant 17-45286703-T-G is Benign according to our data. Variant chr17-45286703-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 544326.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MAP3K14	NM_003954.5 linkuse as main transcript	c.880A>C	p.Lys294Gln	missense_variant	5/16	ENST00000344686.8	NP_003945.2	Q99558Q68D39
MAP3K14	XM_047436997.1 linkuse as main transcript	c.880A>C	p.Lys294Gln	missense_variant	5/15		XP_047292953.1
MAP3K14	XM_047436998.1 linkuse as main transcript	c.880A>C	p.Lys294Gln	missense_variant	6/16		XP_047292954.1
MAP3K14	XM_011525441.3 linkuse as main transcript	c.880A>C	p.Lys294Gln	missense_variant	6/17		XP_011523743.1	Q99558

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
MAP3K14	ENST00000344686.8 linkuse as main transcript	c.880A>C	p.Lys294Gln	missense_variant	5/16	1	NM_003954.5	ENSP00000478552.1	Q99558
MAP3K14	ENST00000376926.8 linkuse as main transcript	c.880A>C	p.Lys294Gln	missense_variant	4/15	1		ENSP00000482657.1	Q99558
MAP3K14	ENST00000617331.3 linkuse as main transcript	c.880A>C	p.Lys294Gln	missense_variant	6/17	5		ENSP00000480974.3	Q99558A0A087WXF1

Frequencies

GnomAD3 genomes

AF:

0.00116

AC:

176

AN:

152130

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00394

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000655

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:

0.00

Gnomad OTH

AF:

0.000955

GnomAD3 exomes

AF:

0.000187

AC:

AN:

240214

Hom.:

AF XY:

0.000161

AC XY:

AN XY:

130292

show subpopulations

Gnomad AFR exome

AF:

0.00274

Gnomad AMR exome

AF:

0.000179

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000988

AC:

144

AN:

1457792

Hom.:

Cov.:

AF XY:

0.0000980

AC XY:

AN XY:

724698

show subpopulations

Gnomad4 AFR exome

AF:

0.00314

Gnomad4 AMR exome

AF:

0.000159

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000117

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.000498

GnomAD4 genome

AF:

0.00116

AC:

177

AN:

152248

Hom.:

Cov.:

AF XY:

0.00134

AC XY:

100

AN XY:

74444

show subpopulations

Gnomad4 AFR

AF:

0.00395

Gnomad4 AMR

AF:

0.000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000945

Alfa

AF:

0.000144

Hom.:

Bravo

AF:

0.00126

ESP6500AA

AF:

0.00356

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000306

AC:

Asia WGS

AF:

0.00144

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2023	MAP3K14: BP4 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

NIK deficiency

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 27, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.71

CADD

Benign

1.9

DANN

Benign

0.25

DEOGEN2

Benign

0.20

T;T;T

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.011

LIST_S2

Benign

0.13

.;T;.

MetaRNN

Benign

0.0039

T;T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

-0.81

N;N;N

PrimateAI

Benign

0.29

REVEL

Benign

0.070

Sift4G

Benign

0.48

.;T;T

Polyphen

0.0

B;B;B

Vest4

0.086, 0.083

MVP

0.095

ClinPred

0.024

GERP RS

-1.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.074

gMVP

0.21

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