rs1877316

Variant names:

• chr17-63689520-C-A
• rs1877316
• NM_002401.5:c.872-24C>A

Your query was ambiguous. Multiple possible variants found:

• chr17-63689520-C-A
• chr17-63689520-C-G
• chr17-63689520-C-T

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.872-24C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.262 in 1,600,324 control chromosomes in the GnomAD database, including 56,831 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.27 (6010 hom., cov: 32)
  • Exomes 𝑓: 0.26 (50821 hom.)
• Consequence: MAP3K3 NM_002401.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -5.31
• Publications: 18 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=-0.77).
• BP6: Variant 17-63689520-C-A is Benign according to our data. Variant chr17-63689520-C-A is described in ClinVar as Benign. ClinVar VariationId is 1248554.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.341 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.872-24C>A		intron	N/A	NP_002392.2
	MAP3K3	NM_203351.3		c.965-24C>A		intron	N/A	NP_976226.1	Q99759-2
	MAP3K3	NM_001363768.2		c.953-24C>A		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.872-24C>A		intron	N/A	ENSP00000354485.4	Q99759-1
	MAP3K3	ENST00000361357.7	TSL:1	c.965-24C>A		intron	N/A	ENSP00000354927.3	Q99759-2
	MAP3K3	ENST00000579585.5	TSL:1	c.965-24C>A		intron	N/A	ENSP00000461988.1	Q99759-2

Frequencies

GnomAD3 genomes AF: 0.273 AC: 41499 AN: 151972 Hom.: 5997 Cov.: 32

Gnomad AFR AF: 0.345

Gnomad AMI AF: 0.269

Gnomad AMR AF: 0.207

Gnomad ASJ AF: 0.271

Gnomad EAS AF: 0.0553

Gnomad SAS AF: 0.165

Gnomad FIN AF: 0.204

Gnomad MID AF: 0.354

Gnomad NFE AF: 0.279

Gnomad OTH AF: 0.270

GnomAD2 exomes AF: 0.235 AC: 55516 AN: 235772 AF XY: 0.234

Gnomad AFR exome AF: 0.347

Gnomad AMR exome AF: 0.200

Gnomad ASJ exome AF: 0.271

Gnomad EAS exome AF: 0.0467

Gnomad FIN exome AF: 0.219

Gnomad NFE exome AF: 0.279

Gnomad OTH exome AF: 0.244

GnomAD4 exome AF: 0.260 AC: 376992 AN: 1448232 Hom.: 50821 Cov.: 30 AF XY: 0.258 AC XY: 185748 AN XY: 719230

African (AFR) AF: 0.346 AC: 11485 AN: 33218

American (AMR) AF: 0.203 AC: 8887 AN: 43750

Ashkenazi Jewish (ASJ) AF: 0.270 AC: 6918 AN: 25586

East Asian (EAS) AF: 0.0507 AC: 1992 AN: 39304

South Asian (SAS) AF: 0.177 AC: 14956 AN: 84352

European-Finnish (FIN) AF: 0.224 AC: 11738 AN: 52366

Middle Eastern (MID) AF: 0.287 AC: 1641 AN: 5720

European-Non Finnish (NFE) AF: 0.276 AC: 304708 AN: 1104064

Other (OTH) AF: 0.245 AC: 14667 AN: 59872

GnomAD4 genome AF: 0.273 AC: 41539 AN: 152092 Hom.: 6010 Cov.: 32 AF XY: 0.267 AC XY: 19817 AN XY: 74342

African (AFR) AF: 0.345 AC: 14314 AN: 41456

American (AMR) AF: 0.206 AC: 3156 AN: 15306

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

East Asian (EAS) AF: 0.0554 AC: 287 AN: 5178

South Asian (SAS) AF: 0.163 AC: 788 AN: 4828

European-Finnish (FIN) AF: 0.204 AC: 2163 AN: 10584

Middle Eastern (MID) AF: 0.364 AC: 107 AN: 294

European-Non Finnish (NFE) AF: 0.279 AC: 18974 AN: 67954

Other (OTH) AF: 0.267 AC: 563 AN: 2108

Alfa AF: 0.265 Hom.: 7202

Bravo AF: 0.275

Asia WGS AF: 0.137 AC: 478 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	-0.77
CADD	Benign	0.0020
DANN	Benign	0.88
PhyloP100		-5.3
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1877316; hg19: chr17-61766880; COSMIC: COSV107464881; COSMIC: COSV107464881;