NM_002401.5:c.127-256_127-247delGTCACAGCAT

Variant names:

• chr17-63645770-AACAGCATGTC-A
• rs58194636
• NM_002401.5:c.127-256_127-247delGTCACAGCAT

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_002401.5(MAP3K3):​c.127-256_127-247delGTCACAGCAT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.234 in 152,016 control chromosomes in the GnomAD database, including 4,301 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.23 (4301 hom., cov: 25)
• Consequence: MAP3K3 NM_002401.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.194
• Publications: 1 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 -10 ACMG points.

• BP6: Variant 17-63645770-AACAGCATGTC-A is Benign according to our data. Variant chr17-63645770-AACAGCATGTC-A is described in ClinVar as Benign. ClinVar VariationId is 1253109.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.275 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.127-256_127-247delGTCACAGCAT		intron	N/A	NP_002392.2
	MAP3K3	NM_203351.3		c.220-256_220-247delGTCACAGCAT		intron	N/A	NP_976226.1	Q99759-2
	MAP3K3	NM_001363768.2		c.220-256_220-247delGTCACAGCAT		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.127-263_127-254delACAGCATGTC		intron	N/A	ENSP00000354485.4	Q99759-1
	MAP3K3	ENST00000361357.7	TSL:1	c.220-263_220-254delACAGCATGTC		intron	N/A	ENSP00000354927.3	Q99759-2
	MAP3K3	ENST00000579585.5	TSL:1	c.220-263_220-254delACAGCATGTC		intron	N/A	ENSP00000461988.1	Q99759-2

Frequencies

GnomAD3 genomes AF: 0.234 AC: 35524 AN: 151896 Hom.: 4298 Cov.: 25

Gnomad AFR AF: 0.209

Gnomad AMI AF: 0.264

Gnomad AMR AF: 0.194

Gnomad ASJ AF: 0.271

Gnomad EAS AF: 0.0554

Gnomad SAS AF: 0.165

Gnomad FIN AF: 0.204

Gnomad MID AF: 0.328

Gnomad NFE AF: 0.278

Gnomad OTH AF: 0.247

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

GnomAD4 genome AF: 0.234 AC: 35526 AN: 152016 Hom.: 4301 Cov.: 25 AF XY: 0.228 AC XY: 16968 AN XY: 74322

African (AFR) AF: 0.209 AC: 8670 AN: 41470

American (AMR) AF: 0.193 AC: 2953 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.271 AC: 938 AN: 3464

East Asian (EAS) AF: 0.0555 AC: 288 AN: 5188

South Asian (SAS) AF: 0.164 AC: 792 AN: 4830

European-Finnish (FIN) AF: 0.204 AC: 2164 AN: 10594

Middle Eastern (MID) AF: 0.336 AC: 98 AN: 292

European-Non Finnish (NFE) AF: 0.278 AC: 18869 AN: 67882

Other (OTH) AF: 0.244 AC: 515 AN: 2108

Alfa AF: 0.256 Hom.: 608

Bravo AF: 0.231

Asia WGS AF: 0.126 AC: 440 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.19
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs58194636; hg19: chr17-61723130;