rs35659744

Variant names:

Variant summary

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

The NM_004672.5(MAP3K6):c.1866C>A(p.Asn622Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.267 in 1,605,104 control chromosomes in the GnomAD database, including 61,678 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.21 ( 4302 hom., cov: 33)

Exomes 𝑓: 0.27 ( 57376 hom. )

Consequence

MAP3K6
NM_004672.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.183

Publications

41 publications found

Variant links:

Genes affected

MAP3K6 (HGNC:6858): (mitogen-activated protein kinase kinase kinase 6) This gene encodes a serine/threonine protein kinase that forms a component of protein kinase-mediated signal transduction cascades. The encoded kinase participates in the regulation of vascular endothelial growth factor (VEGF) expression. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2014]

MAP3K6 Gene-Disease associations (from GenCC):

hereditary diffuse gastric adenocarcinoma
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
gastric cancer
Inheritance: Unknown Classification: LIMITED Submitted by: Laboratory for Molecular Medicine

MAP3K6 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 (MetaRNN=0.0039737225).

BP6

Variant 1-27360975-G-T is Benign according to our data. Variant chr1-27360975-G-T is described in ClinVar as Benign. ClinVar VariationId is 403071.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.299 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAP3K6	NM_004672.5 link	c.1866C>A	p.Asn622Lys	missense_variant	Exon 14 of 29	ENST00000357582.3	NP_004663.3	O95382-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MAP3K6	ENST00000357582.3 link	c.1866C>A	p.Asn622Lys	missense_variant	Exon 14 of 29	1	NM_004672.5	ENSP00000350195.2	O95382-1
MAP3K6	ENST00000374040.7 link	c.1842C>A	p.Asn614Lys	missense_variant	Exon 13 of 28	1		ENSP00000363152.2	O95382-3
MAP3K6	ENST00000493901.6 link	n.1470C>A		non_coding_transcript_exon_variant	Exon 12 of 27	5
MAP3K6	ENST00000671291.1 link	n.700C>A		non_coding_transcript_exon_variant	Exon 7 of 20

Frequencies

GnomAD3 genomes

AF:

0.211

AC:

32022

AN:

152114

Hom.:

4303

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0578

Gnomad AMI

AF:

0.304

Gnomad AMR

AF:

0.199

Gnomad ASJ

AF:

0.380

Gnomad EAS

AF:

0.0961

Gnomad SAS

AF:

0.147

Gnomad FIN

AF:

0.245

Gnomad MID

AF:

0.320

Gnomad NFE

AF:

0.303

Gnomad OTH

AF:

0.241

GnomAD2 exomes

AF:

0.226

AC:

53166

AN:

235204

AF XY:

0.231

show subpopulations

Gnomad AFR exome

AF:

0.0497

Gnomad AMR exome

AF:

0.140

Gnomad ASJ exome

AF:

0.368

Gnomad EAS exome

AF:

0.0936

Gnomad FIN exome

AF:

0.246

Gnomad NFE exome

AF:

0.303

Gnomad OTH exome

AF:

0.255

GnomAD4 exome

AF:

0.273

AC:

396544

AN:

1452872

Hom.:

57376

Cov.:

AF XY:

0.270

AC XY:

195144

AN XY:

721832

show subpopulations

African (AFR)

AF:

0.0494

AC:

1645

AN:

33318

American (AMR)

AF:

0.146

AC:

6458

AN:

44110

Ashkenazi Jewish (ASJ)

AF:

0.370

AC:

9564

AN:

25816

East Asian (EAS)

AF:

0.0981

AC:

3873

AN:

39484

South Asian (SAS)

AF:

0.154

AC:

13111

AN:

85410

European-Finnish (FIN)

AF:

0.245

AC:

12698

AN:

51756

Middle Eastern (MID)

AF:

0.277

AC:

1585

AN:

5720

European-Non Finnish (NFE)

AF:

0.300

AC:

332161

AN:

1107396

Other (OTH)

AF:

0.258

AC:

15449

AN:

59862

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

17072

34144

51215

68287

85359

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

10608

21216

31824

42432

53040

<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:

0.210

AC:

32016

AN:

152232

Hom.:

4302

Cov.:

AF XY:

0.207

AC XY:

15426

AN XY:

74420

show subpopulations

African (AFR)

AF:

0.0577

AC:

2399

AN:

41576

American (AMR)

AF:

0.199

AC:

3038

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.380

AC:

1319

AN:

3470

East Asian (EAS)

AF:

0.0955

AC:

493

AN:

5162

South Asian (SAS)

AF:

0.148

AC:

714

AN:

4828

European-Finnish (FIN)

AF:

0.245

AC:

2591

AN:

10596

Middle Eastern (MID)

AF:

0.316

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.303

AC:

20591

AN:

67980

Other (OTH)

AF:

0.237

AC:

501

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1225

2449

3674

4898

6123

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

350

700

1050

1400

1750

<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:

0.261

Hom.:

8966

Bravo

AF:

0.203

TwinsUK

AF:

0.297

AC:

1103

ALSPAC

AF:

0.306

AC:

1178

ESP6500AA

AF:

0.0572

AC:

243

ESP6500EA

AF:

0.296

AC:

2513

ExAC

AF:

0.223

AC:

26852

Asia WGS

AF:

0.0940

AC:

328

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

MAP3K6-related disorder

Benign:1

Oct 21, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.64

BayesDel_noAF

Benign

-0.55

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.075

.;T;T

Eigen

Benign

-0.55

Eigen_PC

Benign

-0.61

FATHMM_MKL

Benign

0.032

LIST_S2

Benign

0.75

T;.;T

MetaRNN

Benign

0.0040

T;T;T

MetaSVM

Benign

-0.98

MutationAssessor

Uncertain

2.3

.;M;M

PhyloP100

0.18

PrimateAI

Benign

0.45

PROVEAN

Uncertain

-2.5

D;D;D

REVEL

Benign

0.039

Sift

Benign

0.10

T;T;T

Sift4G

Benign

0.15

T;T;T

Polyphen

0.0030

B;B;B

Vest4

0.043

MutPred

0.35

.;Gain of ubiquitination at N622 (P = 0.0066);Gain of ubiquitination at N622 (P = 0.0066);

MPC

1.2

ClinPred

0.0038

GERP RS

-0.34

Varity_R

0.13

gMVP

0.41

Mutation Taster

=98/2

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