Genetic Variant MAP3K11:p.Ala653Thr (chr11-65599643-C-T) – ACMG Classification: Likely_benign (-3 pts)

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 1P and 4B. PP2BS2

The NM_002419.4(MAP3K11):c.1957G>A(p.Ala653Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000234 in 1,536,402 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

MAP3K11
NM_002419.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.89

Publications

1 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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 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).

BS2

High AC in GnomAd4 at 17 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.1957G>A	p.Ala653Thr	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.1957G>A	p.Ala653Thr	missense	Exon 9 of 10	ENSP00000309597.3	Q16584-1
MAP3K11	ENST00000850884.1		c.1957G>A	p.Ala653Thr	missense	Exon 9 of 10	ENSP00000520962.1
MAP3K11	ENST00000941368.1		c.1954G>A	p.Ala652Thr	missense	Exon 9 of 10	ENSP00000611427.1

Frequencies

GnomAD3 genomes

AF:

0.000112

AC:

AN:

152142

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000917

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.0000644

AC:

AN:

139724

AF XY:

0.0000896

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000403

Gnomad ASJ exome

AF:

0.00

Gnomad EAS 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:

0.0000137

AC:

AN:

1384260

Hom.:

Cov.:

AF XY:

0.0000161

AC XY:

AN XY:

684196

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

29918

American (AMR)

AF:

0.000269

AC:

AN:

33420

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24382

East Asian (EAS)

AF:

0.00

AC:

AN:

35350

South Asian (SAS)

AF:

0.00

AC:

AN:

79716

European-Finnish (FIN)

AF:

0.00

AC:

AN:

41798

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4208

European-Non Finnish (NFE)

AF:

0.00000835

AC:

AN:

1078210

Other (OTH)

AF:

0.0000175

AC:

AN:

57258

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.520

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:

0.000112

AC:

AN:

152142

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

AN XY:

74324

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41440

American (AMR)

AF:

0.000917

AC:

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68000

Other (OTH)

AF:

0.000478

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000982

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

Uncertain

0.47

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.20

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.50

Eigen

Uncertain

0.45

Eigen_PC

Uncertain

0.42

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.82

M_CAP

Pathogenic

0.40

MetaRNN

Uncertain

0.50

MetaSVM

Uncertain

0.0027

MutationAssessor

Benign

0.69

PhyloP100

3.9

PrimateAI

Pathogenic

0.92

PROVEAN

Benign

-2.4

REVEL

Benign

0.26

Sift

Benign

0.048

Sift4G

Uncertain

0.028

Polyphen

1.0

Vest4

0.55

MutPred

0.25

Gain of phosphorylation at A653 (P = 0.0915)

MVP

0.88

MPC

0.20

ClinPred

0.29

GERP RS

5.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.18

gMVP

0.52

Mutation Taster

=63/37

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.14

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over