MAP3K3 p.Met31Leu

Variant names:

• chr17-63632767-A-T
• NM_002401.5:c.91A>T
• MAP3K3 p.Met31Leu

Your query was ambiguous. Multiple possible variants found:

• chr17-63632767-A-T
• chr17-63632767-A-C
• chr17-63632767-ATG-TTA
• chr17-63632767-ATG-CTT
• chr17-63632767-ATG-CTC
• chr17-63632767-ATG-CTA

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002401.5(MAP3K3):​c.91A>T​(p.Met31Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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)
• Consequence: MAP3K3 NM_002401.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.02
• Publications: 0 publications found

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]

ACMG classification

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=0.08973956).

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

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

Ensembl Transcripts

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

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

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	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	16
DANN	Benign	0.83
DEOGEN2	Benign	0.018	T
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.33
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.0091	T
MetaRNN	Benign	0.090	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.9	M
PhyloP100		2.0
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-0.47	N
REVEL	Benign	0.15
Sift	Benign	0.66	T
Sift4G	Benign	0.62	T
Varity_R		0.12
gMVP		0.26

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr17-61710127;