rs8081612

Variant names:

• chr17-63647335-C-T
• rs8081612
• NM_002401.5:c.167+1261C>T

Variant summary

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

The NM_002401.5(MAP3K3):​c.167+1261C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.379 in 152,128 control chromosomes in the GnomAD database, including 14,312 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 0.38 (14312 hom., cov: 32)
• Consequence: MAP3K3 NM_002401.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.316
• Publications: 15 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=-0.92).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.704 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.167+1261C>T		intron	N/A	NP_002392.2
	MAP3K3	NM_203351.3		c.260+1261C>T		intron	N/A	NP_976226.1	Q99759-2
	MAP3K3	NM_001363768.2		c.260+1261C>T		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.167+1261C>T		intron	N/A	ENSP00000354485.4	Q99759-1
	MAP3K3	ENST00000361357.7	TSL:1	c.260+1261C>T		intron	N/A	ENSP00000354927.3	Q99759-2
	MAP3K3	ENST00000579585.5	TSL:1	c.260+1261C>T		intron	N/A	ENSP00000461988.1	Q99759-2

Frequencies

GnomAD3 genomes AF: 0.379 AC: 57576 AN: 152010 Hom.: 14259 Cov.: 32

Gnomad AFR AF: 0.710

Gnomad AMI AF: 0.267

Gnomad AMR AF: 0.248

Gnomad ASJ AF: 0.281

Gnomad EAS AF: 0.0557

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

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

GnomAD4 genome AF: 0.379 AC: 57673 AN: 152128 Hom.: 14312 Cov.: 32 AF XY: 0.369 AC XY: 27485 AN XY: 74394

African (AFR) AF: 0.711 AC: 29484 AN: 41476

American (AMR) AF: 0.248 AC: 3789 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.281 AC: 974 AN: 3472

East Asian (EAS) AF: 0.0558 AC: 289 AN: 5180

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

European-Finnish (FIN) AF: 0.205 AC: 2172 AN: 10584

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

European-Non Finnish (NFE) AF: 0.281 AC: 19079 AN: 67980

Other (OTH) AF: 0.344 AC: 726 AN: 2108

Alfa AF: 0.313 Hom.: 11711

Bravo AF: 0.398

Asia WGS AF: 0.162 AC: 566 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	7.8
DANN	Benign	0.38
PhyloP100		0.32
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

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

Other links and lift over

dbSNP: rs8081612;

hg19: chr17-61724695;