Genetic Variant MAP3K3:p.Met31Leu (chr17-63632767-A-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_002401.5(MAP3K3):c.91A>C(p.Met31Leu) 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 1,461,838 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M31V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

MAP3K3
NM_002401.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.02

Publications

0 publications found

Variant links:

Genes affected

MAP3K3 (HGNC:6855): (mitogen-activated protein kinase kinase kinase 3) This gene product is a 626-amino acid polypeptide that is 96.5% identical to mouse Mekk3. Its catalytic domain is closely related to those of several other kinases, including mouse Mekk2, tobacco NPK, and yeast Ste11. Northern blot analysis revealed a 4.6-kb transcript that appears to be ubiquitously expressed. This protein directly regulates the stress-activated protein kinase (SAPK) and extracellular signal-regulated protein kinase (ERK) pathways by activating SEK and MEK1/2 respectively; it does not regulate the p38 pathway. In cotransfection assays, it enhanced transcription from a nuclear factor kappa-B (NFKB)-dependent reporter gene, consistent with a role in the SAPK pathway. Alternatively spliced transcript variants encoding distinct isoforms have been observed. [provided by RefSeq, Jul 2008]

MAP3K3 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.09071392).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002401.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MAP3K3	NM_002401.5	MANE Select	c.91A>C	p.Met31Leu	missense	Exon 2 of 16	NP_002392.2
MAP3K3	NM_203351.3		c.91A>C	p.Met31Leu	missense	Exon 2 of 17	NP_976226.1	Q99759-2
MAP3K3	NM_001363768.2		c.91A>C	p.Met31Leu	missense	Exon 2 of 17	NP_001350697.1	J3QRB6

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MAP3K3	ENST00000361733.8	TSL:1 MANE Select	c.91A>C	p.Met31Leu	missense	Exon 2 of 16	ENSP00000354485.4	Q99759-1
MAP3K3	ENST00000361357.7	TSL:1	c.91A>C	p.Met31Leu	missense	Exon 2 of 17	ENSP00000354927.3	Q99759-2
MAP3K3	ENST00000579585.5	TSL:1	c.91A>C	p.Met31Leu	missense	Exon 3 of 18	ENSP00000461988.1	Q99759-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461838

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727236

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53410

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111980

Other (OTH)

AF:

0.00

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

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 v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.079

BayesDel_addAF

Benign

-0.043

BayesDel_noAF

Benign

-0.30

CADD

Benign

(source)

DANN

Benign

0.83

DEOGEN2

Benign

0.018

Eigen

Benign

-0.50

Eigen_PC

Benign

-0.33

FATHMM_MKL

Uncertain

0.79

LIST_S2

Benign

0.83

M_CAP

Benign

0.0090

MetaRNN

Benign

0.091

MetaSVM

Benign

-0.92

MutationAssessor

Benign

1.9

PhyloP100

2.0

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-0.47

REVEL

Benign

0.16

Sift

Benign

0.66

Sift4G

Benign

0.62

Polyphen

0.0

Vest4

0.43

MutPred

0.19

Gain of methylation at K32 (P = 0.031)

MVP

0.69

MPC

0.089

ClinPred

0.12

GERP RS

1.4

Varity_R

0.12

gMVP

0.26

Mutation Taster

=94/6

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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