17-63691212-C-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2 PP2 PP3 PP5_Very_Strong

The NM_002401.5(MAP3K3):c.1323C>G(p.Ile441Met) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MAP3K3 NM_002401.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 0.937

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]

STRADA (HGNC:30172): (STE20 related adaptor alpha) The protein encoded by this gene contains a STE20-like kinase domain, but lacks several residues that are critical for catalytic activity, so it is termed a 'pseudokinase'. The protein forms a heterotrimeric complex with serine/threonine kinase 11 (STK11, also known as LKB1) and the scaffolding protein calcium binding protein 39 (CAB39, also known as MO25). The protein activates STK11 leading to the phosphorylation of both proteins and excluding STK11 from the nucleus. The protein is necessary for STK11-induced G1 cell cycle arrest. A mutation in this gene has been shown to result in polyhydramnios, megalencephaly, and symptomatic epilepsy (PMSE) syndrome. Multiple transcript variants encoding different isoforms have been found for this gene. Additional transcript variants have been described but their full-length nature is not known. [provided by RefSeq, Sep 2009]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, MAP3K3
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.812
• PP5: Variant 17-63691212-C-G is Pathogenic according to our data. Variant chr17-63691212-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1691386.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MAP3K3	NM_002401.5	c.1323C>G	p.Ile441Met	missense_variant	13/16	ENST00000361733.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAP3K3	ENST00000361733.8	c.1323C>G	p.Ile441Met	missense_variant	13/16	1	NM_002401.5	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Verrucous hemangioma Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital

Jan 12, 2021

This variant has previously been reported in affected tissues in 6/10 individuals with verrucous venous malformations (PMID: 25728774). The variant has not been reported in large population studies (Genome Aggregation Database v2.1.1). To date, no somatic mutation affecting p.Ile441 has been reported in COSMIC, the catalog of somatic mutation in cancer, nor the NCI Genomic Data Commons database. -

Verrucous venous malformation Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Clinical Genomics Laboratory, Washington University in St. Louis

Aug 27, 2023

The MAP3K3 c.1323C>G (p.Ile441Met) variant was identified at an allelic fraction consistent with somatic origin. This variant has been reported in nine individuals affected with cerebral cavernous malformations (CCMs) (Weng J et al., PMID: 33891857; Ren J et al., PMID: 36917268) and three individuals affected with verrucous venous malformation (Couto JA et al., PMID: 25728774). MAP3K3 c.1323C>G (p.Ile441Met) has been reported in the ClinVar database as pathogenic by one submitter (ClinVar ID: 1691386). This variant is absent from the general population (gnomAD v.3.1.2), indicating it is not a common variant. Functional studies using animal models generated with this variant expressed intracranial lesions that resemble human CCMs (Ren J et al., PMID: 36917268). Furthermore, studies using animals and cell lines demonstrated hyperactivation of downstream signaling pathway (Weng J et al., PMID: 33891857; Huo R et al., PMID: 36090889). Based on an internally developed protocol informed by the ACMG/AMP guidelines (Richards S et al., PMID: 25741868), MAP3K3 c.1323C>G (p.Ile441Met) variant is classified as likely pathogenic -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Uncertain	0.045	T
BayesDel_noAF	Benign	-0.17
Cadd	Pathogenic	27
Dann	Uncertain	1.0
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.89	D
M_CAP	Benign	0.044	D
MetaRNN	Pathogenic	0.81	D;D;D;D;D
MetaSVM	Benign	-0.74	T
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.72	T
Sift4G	Pathogenic	0.0010	D;D;D;D;D
Polyphen		1.0	D;.;D;D;.
Vest4		0.86
MutPred		0.66		.;.;Gain of phosphorylation at Y445 (P = 0.0969);.;.;
MVP		0.65
MPC		1.8
ClinPred		0.98	D
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.94
gMVP		0.62

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-61768572;