rs11658329

Variant names:

• chr17-63685671-G-C
• rs11658329
• NM_002401.5:c.710+81G>C

Your query was ambiguous. Multiple possible variants found:

• chr17-63685671-G-C
• chr17-63685671-G-A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002401.5(MAP3K3):​c.710+81G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.283 in 1,148,490 control chromosomes in the GnomAD database, including 53,947 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.38 (14280 hom., cov: 32)
  • Exomes 𝑓: 0.27 (39667 hom.)
• Consequence: MAP3K3 NM_002401.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.240
• Publications: 37 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]

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]

STRADA Gene-Disease associations (from GenCC):

• polyhydramnios, megalencephaly, and symptomatic epilepsy

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet, PanelApp Australia

LOC101927898 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 17-63685671-G-C is Benign according to our data. Variant chr17-63685671-G-C is described in ClinVar as Benign. ClinVar VariationId is 1181474.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.703 is higher than 0.05.

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.710+81G>C		intron	N/A	NP_002392.2
	MAP3K3	NM_203351.3		c.803+81G>C		intron	N/A	NP_976226.1	Q99759-2
	MAP3K3	NM_001363768.2		c.791+93G>C		intron	N/A	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.710+81G>C		intron	N/A	ENSP00000354485.4	Q99759-1
	MAP3K3	ENST00000361357.7	TSL:1	c.803+81G>C		intron	N/A	ENSP00000354927.3	Q99759-2
	MAP3K3	ENST00000579585.5	TSL:1	c.803+81G>C		intron	N/A	ENSP00000461988.1	Q99759-2

Frequencies

GnomAD3 genomes AF: 0.378 AC: 57542 AN: 152036 Hom.: 14233 Cov.: 32

Gnomad AFR AF: 0.709

Gnomad AMI AF: 0.268

Gnomad AMR AF: 0.248

Gnomad ASJ AF: 0.280

Gnomad EAS AF: 0.0552

Gnomad SAS AF: 0.168

Gnomad FIN AF: 0.205

Gnomad MID AF: 0.380

Gnomad NFE AF: 0.281

Gnomad OTH AF: 0.348

GnomAD4 exome AF: 0.268 AC: 267322 AN: 996336 Hom.: 39667 AF XY: 0.264 AC XY: 135537 AN XY: 512912

African (AFR) AF: 0.717 AC: 17474 AN: 24368

American (AMR) AF: 0.225 AC: 9774 AN: 43516

Ashkenazi Jewish (ASJ) AF: 0.281 AC: 6524 AN: 23202

East Asian (EAS) AF: 0.0503 AC: 1874 AN: 37244

South Asian (SAS) AF: 0.180 AC: 13764 AN: 76460

European-Finnish (FIN) AF: 0.224 AC: 11780 AN: 52598

Middle Eastern (MID) AF: 0.309 AC: 1486 AN: 4802

European-Non Finnish (NFE) AF: 0.279 AC: 192363 AN: 689402

Other (OTH) AF: 0.275 AC: 12283 AN: 44744

GnomAD4 genome AF: 0.379 AC: 57632 AN: 152154 Hom.: 14280 Cov.: 32 AF XY: 0.369 AC XY: 27454 AN XY: 74384

African (AFR) AF: 0.709 AC: 29430 AN: 41484

American (AMR) AF: 0.248 AC: 3786 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.280 AC: 972 AN: 3470

East Asian (EAS) AF: 0.0553 AC: 287 AN: 5186

South Asian (SAS) AF: 0.167 AC: 804 AN: 4824

European-Finnish (FIN) AF: 0.205 AC: 2172 AN: 10596

Middle Eastern (MID) AF: 0.391 AC: 115 AN: 294

European-Non Finnish (NFE) AF: 0.281 AC: 19098 AN: 67994

Other (OTH) AF: 0.345 AC: 725 AN: 2104

Alfa AF: 0.340 Hom.: 1442

Bravo AF: 0.397

Asia WGS AF: 0.162 AC: 565 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	1.4
DANN	Benign	0.48
PhyloP100		-0.24
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs11658329; hg19: chr17-61763031; COSMIC: COSV62280641; COSMIC: COSV62280641;