chr17-63685671-G-C

Position:

• chr17-63685671-G-C

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.710+81G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.283 in 1,148,490 control chromosomes in the GnomAD database, including 53,947 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.38 (14280 hom., cov: 32)
  • Exomes 𝑓: 0.27 (39667 hom.)
• Consequence: MAP3K3 NM_002401.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.240

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=-0.92).
• BP6: Variant 17-63685671-G-C is Benign according to our data. Variant chr17-63685671-G-C is described in ClinVar as [Benign]. Clinvar id is 1181474.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.703 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MAP3K3	NM_002401.5	c.710+81G>C		intron_variant		ENST00000361733.8	NP_002392.2
LOC101927898	XR_243740.4	n.609-2913C>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAP3K3	ENST00000361733.8	c.710+81G>C		intron_variant		1	NM_002401.5	ENSP00000354485	A1

Frequencies

GnomAD3 genomes AF: 0.378 AC: 57542 AN: 152036 Hom.: 14233 Cov.: 32

Gnomad AFR AF: 0.709

Gnomad AMI AF: 0.268

Gnomad AMR AF: 0.248

Gnomad ASJ AF: 0.280

Gnomad EAS AF: 0.0552

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

GnomAD4 exome AF: 0.268 AC: 267322 AN: 996336 Hom.: 39667 AF XY: 0.264 AC XY: 135537 AN XY: 512912

Gnomad4 AFR exome AF: 0.717

Gnomad4 AMR exome AF: 0.225

Gnomad4 ASJ exome AF: 0.281

Gnomad4 EAS exome AF: 0.0503

Gnomad4 SAS exome AF: 0.180

Gnomad4 FIN exome AF: 0.224

Gnomad4 NFE exome AF: 0.279

Gnomad4 OTH exome AF: 0.275

GnomAD4 genome AF: 0.379 AC: 57632 AN: 152154 Hom.: 14280 Cov.: 32 AF XY: 0.369 AC XY: 27454 AN XY: 74384

Gnomad4 AFR AF: 0.709

Gnomad4 AMR AF: 0.248

Gnomad4 ASJ AF: 0.280

Gnomad4 EAS AF: 0.0553

Gnomad4 SAS AF: 0.167

Gnomad4 FIN AF: 0.205

Gnomad4 NFE AF: 0.281

Gnomad4 OTH AF: 0.345

Alfa AF: 0.340 Hom.: 1442

Bravo AF: 0.397

Asia WGS AF: 0.162 AC: 565 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	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 19, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	1.4
DANN	Benign	0.48
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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

Publications

LitVar

Other links and lift over

dbSNP: rs11658329; hg19: chr17-61763031; COSMIC: COSV62280641; COSMIC: COSV62280641;