17-63689520-C-A

Position:

• chr17-63689520-C-A

Variant summary

Our verdict is Benign. Variant got -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

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]

LOC101927898 (HGNC:):

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]

ACMG classification

Verdict is Benign. Variant got -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MAP3K3	NM_002401.5	c.872-24C>A		intron_variant		ENST00000361733.8	NP_002392.2
LOC101927898	XR_243740.4	n.526-345G>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAP3K3	ENST00000361733.8	c.872-24C>A		intron_variant		1	NM_002401.5	ENSP00000354485	A1

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

GnomAD3 exomes AF: 0.235 AC: 55516 AN: 235772 Hom.: 7050 AF XY: 0.234 AC XY: 29803 AN XY: 127298

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 SAS exome AF: 0.175

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

Gnomad4 AFR exome AF: 0.346

Gnomad4 AMR exome AF: 0.203

Gnomad4 ASJ exome AF: 0.270

Gnomad4 EAS exome AF: 0.0507

Gnomad4 SAS exome AF: 0.177

Gnomad4 FIN exome AF: 0.224

Gnomad4 NFE exome AF: 0.276

Gnomad4 OTH exome AF: 0.245

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

Gnomad4 AFR AF: 0.345

Gnomad4 AMR AF: 0.206

Gnomad4 ASJ AF: 0.271

Gnomad4 EAS AF: 0.0554

Gnomad4 SAS AF: 0.163

Gnomad4 FIN AF: 0.204

Gnomad4 NFE AF: 0.279

Gnomad4 OTH AF: 0.267

Alfa AF: 0.261 Hom.: 5333

Bravo AF: 0.275

Asia WGS AF: 0.137 AC: 478 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 19, 2021	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	0.0020
DANN	Benign	0.88

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

Publications

LitVar

Other links and lift over

dbSNP: rs1877316; hg19: chr17-61766880;