17-63685671-G-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.240

Publications

37 publications found

Variant links:

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]

MAP3K3 links:

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: Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, G2P

STRADA links:

LOC101927898 (HGNC:):

LOC101927898 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId 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 rank	MANE	Protein	UniProt
MAP3K3	NM_002401.5 link	c.710+81G>C		intron_variant	Intron 8 of 15	ENST00000361733.8	NP_002392.2	Q99759-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAP3K3	ENST00000361733.8 link	c.710+81G>C		intron_variant	Intron 8 of 15	1	NM_002401.5	ENSP00000354485.4		Q99759-1

Frequencies

GnomAD3 genomes

AF:

0.378

AC:

57542

AN:

152036

Hom.:

14233

Cov.:

show subpopulations

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

show subpopulations

African (AFR)

AF:

0.717

AC:

17474

AN:

24368

American (AMR)

AF:

0.225

AC:

9774

AN:

43516

Ashkenazi Jewish (ASJ)

AF:

0.281

AC:

6524

AN:

23202

East Asian (EAS)

AF:

0.0503

AC:

1874

AN:

37244

South Asian (SAS)

AF:

0.180

AC:

13764

AN:

76460

European-Finnish (FIN)

AF:

0.224

AC:

11780

AN:

52598

Middle Eastern (MID)

AF:

0.309

AC:

1486

AN:

4802

European-Non Finnish (NFE)

AF:

0.279

AC:

192363

AN:

689402

Other (OTH)

AF:

0.275

AC:

12283

AN:

44744

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

9314

18627

27941

37254

46568

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

5046

10092

15138

20184

25230

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.379

AC:

57632

AN:

152154

Hom.:

14280

Cov.:

AF XY:

0.369

AC XY:

27454

AN XY:

74384

show subpopulations

African (AFR)

AF:

0.709

AC:

29430

AN:

41484

American (AMR)

AF:

0.248

AC:

3786

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.280

AC:

972

AN:

3470

East Asian (EAS)

AF:

0.0553

AC:

287

AN:

5186

South Asian (SAS)

AF:

0.167

AC:

804

AN:

4824

European-Finnish (FIN)

AF:

0.205

AC:

2172

AN:

10596

Middle Eastern (MID)

AF:

0.391

AC:

115

AN:

294

European-Non Finnish (NFE)

AF:

0.281

AC:

19098

AN:

67994

Other (OTH)

AF:

0.345

AC:

725

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1520

3040

4559

6079

7599

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

486

972

1458

1944

2430

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jun 19, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.92

CADD

Benign

1.4

(source)

DANN

Benign

0.48

PhyloP100

-0.24

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over