chr17-45267442-T-C

Position:

chr17-45267442-T-C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP2BP4_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. 12/15 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

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

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:):

MAP3K14-AS1 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 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=0.007188499).

BP6

Variant 17-45267442-T-C is Benign according to our data. Variant chr17-45267442-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 478059.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}. Variant chr17-45267442-T-C is described in Lovd as [Likely_benign].

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MAP3K14	NM_003954.5 linkuse as main transcript	c.2290A>G	p.Thr764Ala	missense_variant	12/16	ENST00000344686.8	NP_003945.2	Q99558Q68D39

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAP3K14	ENST00000344686.8 linkuse as main transcript	c.2290A>G	p.Thr764Ala	missense_variant	12/16	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

GnomAD3 exomes

AF:

0.00188

AC:

442

AN:

235416

Hom.:

AF XY:

0.00177

AC XY:

227

AN XY:

128208

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 SAS exome

AF:

0.000136

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

Gnomad4 AFR exome

AF:

0.000630

Gnomad4 AMR exome

AF:

0.000485

Gnomad4 ASJ exome

AF:

0.000155

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000106

Gnomad4 FIN exome

AF:

0.000905

Gnomad4 NFE exome

AF:

0.00375

Gnomad4 OTH exome

AF:

0.00156

GnomAD4 genome

AF:

0.00198

AC:

301

AN:

152334

Hom.:

Cov.:

AF XY:

0.00181

AC XY:

135

AN XY:

74510

show subpopulations

Gnomad4 AFR

AF:

0.000673

Gnomad4 AMR

AF:

0.00144

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000942

Gnomad4 NFE

AF:

0.00350

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.00244

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

Uncertain significance, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Apr 13, 2020

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

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 11, 2024

- -

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

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

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

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