Genetic Variant NM_002419.4:c.2012G>A (chr11-65599588-C-T) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 1P and 6B. PP2BP4_ModerateBS2

The NM_002419.4(MAP3K11):c.2012G>A(p.Arg671His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000283 in 1,519,242 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000027 ( 0 hom. )

Consequence

MAP3K11
NM_002419.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.228

Publications

0 publications found

Variant links:

Genes affected

MAP3K11 (HGNC:6850): (mitogen-activated protein kinase kinase kinase 11) The protein encoded by this gene is a member of the serine/threonine kinase family. This kinase contains a SH3 domain and a leucine zipper-basic motif. This kinase preferentially activates MAPK8/JNK kinase, and functions as a positive regulator of JNK signaling pathway. This kinase can directly phosphorylate, and activates IkappaB kinase alpha and beta, and is found to be involved in the transcription activity of NF-kappaB mediated by Rho family GTPases and CDC42. [provided by RefSeq, Jul 2008]

MAP3K11 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 1 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 1.9036 (below the threshold of 3.09). Trascript score misZ: 0.51103 (below the threshold of 3.09).

BP4

Computational evidence support a benign effect (MetaRNN=0.17545834).

BS2

High AC in GnomAd4 at 6 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002419.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAP3K11	NM_002419.4	MANE Select	c.2012G>A	p.Arg671His	missense	Exon 9 of 10	NP_002410.1	Q16584-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MAP3K11	ENST00000309100.8	TSL:1 MANE Select	c.2012G>A	p.Arg671His	missense	Exon 9 of 10	ENSP00000309597.3	Q16584-1
MAP3K11	ENST00000850884.1		c.2012G>A	p.Arg671His	missense	Exon 9 of 10	ENSP00000520962.1
MAP3K11	ENST00000941368.1		c.2009G>A	p.Arg670His	missense	Exon 9 of 10	ENSP00000611427.1

Frequencies

GnomAD3 genomes

AF:

0.0000395

AC:

AN:

152056

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000386

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000417

AC:

AN:

143734

AF XY:

0.0000489

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000542

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000364

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000271

AC:

AN:

1367186

Hom.:

Cov.:

AF XY:

0.0000296

AC XY:

AN XY:

675512

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

27276

American (AMR)

AF:

0.000106

AC:

AN:

28298

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

20950

East Asian (EAS)

AF:

0.000285

AC:

AN:

35104

South Asian (SAS)

AF:

0.0000137

AC:

AN:

73180

European-Finnish (FIN)

AF:

0.000209

AC:

AN:

47954

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4008

European-Non Finnish (NFE)

AF:

0.0000102

AC:

AN:

1074422

Other (OTH)

AF:

0.0000357

AC:

AN:

55994

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

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

AF:

0.0000395

AC:

AN:

152056

Hom.:

Cov.:

AF XY:

0.0000539

AC XY:

AN XY:

74258

show subpopulations

African (AFR)

AF:

0.0000724

AC:

AN:

41416

American (AMR)

AF:

0.00

AC:

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.000386

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10604

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

67964

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

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:

0.0000712

Hom.:

Bravo

AF:

0.0000378

ExAC

AF:

0.0000350

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.099

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.32

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.31

Eigen

Benign

-0.30

Eigen_PC

Benign

-0.34

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.74

M_CAP

Pathogenic

0.43

MetaRNN

Benign

0.18

MetaSVM

Benign

-0.81

MutationAssessor

Benign

0.55

PhyloP100

0.23

PrimateAI

Uncertain

0.77

PROVEAN

Benign

-1.2

REVEL

Benign

0.15

Sift

Uncertain

0.0010

Sift4G

Benign

0.11

Polyphen

0.80

Vest4

0.27

MutPred

0.20

Loss of methylation at R671 (P = 0.0071)

MVP

0.84

MPC

0.29

ClinPred

0.10

GERP RS

4.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.15

gMVP

0.18

Mutation Taster

=76/24

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over