rs12325866

Variant names:

• chr17-63678614-G-A
• rs12325866
• NM_002401.5:c.503-3152G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002401.5(MAP3K3):​c.503-3152G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.281 in 152,218 control chromosomes in the GnomAD database, including 6,422 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.28 (6422 hom., cov: 33)
• Consequence: MAP3K3 NM_002401.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.191
• Publications: 23 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.365 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAP3K3	NM_002401.5	c.503-3152G>A		intron_variant	Intron 6 of 15	ENST00000361733.8	NP_002392.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAP3K3	ENST00000361733.8	c.503-3152G>A		intron_variant	Intron 6 of 15	1	NM_002401.5	ENSP00000354485.4

Frequencies

GnomAD3 genomes AF: 0.281 AC: 42693 AN: 152098 Hom.: 6407 Cov.: 33

Gnomad AFR AF: 0.370

Gnomad AMI AF: 0.267

Gnomad AMR AF: 0.210

Gnomad ASJ AF: 0.271

Gnomad EAS AF: 0.0554

Gnomad SAS AF: 0.168

Gnomad FIN AF: 0.205

Gnomad MID AF: 0.361

Gnomad NFE AF: 0.280

Gnomad OTH AF: 0.277

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.281 AC: 42736 AN: 152218 Hom.: 6422 Cov.: 33 AF XY: 0.274 AC XY: 20397 AN XY: 74430

African (AFR) AF: 0.370 AC: 15366 AN: 41510

American (AMR) AF: 0.210 AC: 3214 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.271 AC: 942 AN: 3472

East Asian (EAS) AF: 0.0555 AC: 288 AN: 5192

South Asian (SAS) AF: 0.166 AC: 802 AN: 4830

European-Finnish (FIN) AF: 0.205 AC: 2178 AN: 10602

Middle Eastern (MID) AF: 0.371 AC: 109 AN: 294

European-Non Finnish (NFE) AF: 0.280 AC: 19016 AN: 68000

Other (OTH) AF: 0.274 AC: 578 AN: 2112

Alfa AF: 0.275 Hom.: 9961

Bravo AF: 0.284

Asia WGS AF: 0.140 AC: 488 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	2.1
DANN	Benign	0.51
PhyloP100		0.19
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: rs12325866; hg19: chr17-61755974;