17-63666680-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_002401.5(MAP3K3):c.382-260A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.281 in 152,084 control chromosomes in the GnomAD database, including 6,425 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.28 (6425 hom., cov: 32)
• Consequence: MAP3K3 NM_002401.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.77

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

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 17-63666680-A-G is Benign according to our data. Variant chr17-63666680-A-G is described in ClinVar as [Benign]. Clinvar id is 1247823.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.365 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MAP3K3	NM_002401.5	c.382-260A>G		intron_variant		ENST00000361733.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAP3K3	ENST00000361733.8	c.382-260A>G		intron_variant		1	NM_002401.5	A1

Frequencies

GnomAD3 genomes AF: 0.281 AC: 42685 AN: 151964 Hom.: 6410 Cov.: 32

Gnomad AFR AF: 0.369

Gnomad AMI AF: 0.267

Gnomad AMR AF: 0.211

Gnomad ASJ AF: 0.271

Gnomad EAS AF: 0.0554

Gnomad SAS AF: 0.168

Gnomad FIN AF: 0.205

Gnomad MID AF: 0.361

Gnomad NFE AF: 0.280

Gnomad OTH AF: 0.276

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

GnomAD4 genome AF: 0.281 AC: 42728 AN: 152084 Hom.: 6425 Cov.: 32 AF XY: 0.274 AC XY: 20378 AN XY: 74332

Gnomad4 AFR AF: 0.370

Gnomad4 AMR AF: 0.210

Gnomad4 ASJ AF: 0.271

Gnomad4 EAS AF: 0.0555

Gnomad4 SAS AF: 0.166

Gnomad4 FIN AF: 0.205

Gnomad4 NFE AF: 0.280

Gnomad4 OTH AF: 0.273

Alfa AF: 0.289 Hom.: 1031

Bravo AF: 0.284

Asia WGS AF: 0.139 AC: 485 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 19, 2021

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
Cadd	Benign	1.4
Dann	Benign	0.30

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs8070650; hg19: chr17-61744040;