17-63635604-T-C

Variant names:

• chr17-63635604-T-C
• rs7209435
• NM_002401.5:c.126+2802T>C

Variant summary

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

The NM_002401.5(MAP3K3):​c.126+2802T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.381 in 151,952 control chromosomes in the GnomAD database, including 14,373 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 (14373 hom., cov: 32)
• Consequence: MAP3K3 NM_002401.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.521
• Publications: 36 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 = 0.705 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAP3K3	NM_002401.5	c.126+2802T>C		intron_variant	Intron 2 of 15	ENST00000361733.8	NP_002392.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAP3K3	ENST00000361733.8	c.126+2802T>C		intron_variant	Intron 2 of 15	1	NM_002401.5	ENSP00000354485.4

Frequencies

GnomAD3 genomes AF: 0.380 AC: 57738 AN: 151836 Hom.: 14320 Cov.: 32

Gnomad AFR AF: 0.711

Gnomad AMI AF: 0.269

Gnomad AMR AF: 0.249

Gnomad ASJ AF: 0.281

Gnomad EAS AF: 0.0557

Gnomad SAS AF: 0.170

Gnomad FIN AF: 0.207

Gnomad MID AF: 0.380

Gnomad NFE AF: 0.283

Gnomad OTH AF: 0.350

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

GnomAD4 genome AF: 0.381 AC: 57835 AN: 151952 Hom.: 14373 Cov.: 32 AF XY: 0.371 AC XY: 27567 AN XY: 74286

African (AFR) AF: 0.712 AC: 29500 AN: 41444

American (AMR) AF: 0.248 AC: 3794 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.281 AC: 974 AN: 3468

East Asian (EAS) AF: 0.0558 AC: 289 AN: 5176

South Asian (SAS) AF: 0.168 AC: 811 AN: 4814

European-Finnish (FIN) AF: 0.207 AC: 2183 AN: 10536

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

European-Non Finnish (NFE) AF: 0.283 AC: 19195 AN: 67926

Other (OTH) AF: 0.346 AC: 729 AN: 2106

Alfa AF: 0.306 Hom.: 25965

Bravo AF: 0.398

Asia WGS AF: 0.163 AC: 569 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.68
DANN	Benign	0.34
PhyloP100		-0.52
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: rs7209435; hg19: chr17-61712964;