Genetic Variant MAP3K6:p.Lys1125del (chr1-27356738-CCTT-C) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 1P and 6B. PM4_SupportingBP6_ModerateBS2

The NM_004672.5(MAP3K6):c.3373_3375delAAG(p.Lys1125del) variant causes a conservative inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0109 in 1,565,996 control chromosomes in the GnomAD database, including 130 homozygotes. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0081 ( 7 hom., cov: 33)

Exomes 𝑓: 0.011 ( 123 hom. )

Consequence

MAP3K6
NM_004672.5 conservative_inframe_deletion

Scores

Not classified

Clinical Significance

Benign criteria provided, single submitter B:2

Conservation

PhyloP100: 0.219

Publications

3 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: Likely_benign. The variant received -5 ACMG points.

PM4

Nonframeshift variant in NON repetitive region in NM_004672.5. Strenght limited to Supporting due to length of the change: 1aa.

BP6

Variant 1-27356738-CCTT-C is Benign according to our data. Variant chr1-27356738-CCTT-C is described in ClinVar as Benign. ClinVar VariationId is 2638557.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High AC in GnomAd4 at 1229 Unknown,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAP3K6	NM_004672.5 link	c.3373_3375delAAG	p.Lys1125del	conservative_inframe_deletion	Exon 25 of 29	ENST00000357582.3	NP_004663.3	O95382-1
MAP3K6	NM_001297609.2 link	c.3349_3351delAAG	p.Lys1117del	conservative_inframe_deletion	Exon 24 of 28		NP_001284538.1	O95382-3
MAP3K6	XM_047433689.1 link	c.3280_3282delAAG	p.Lys1094del	conservative_inframe_deletion	Exon 26 of 30		XP_047289645.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAP3K6	ENST00000357582.3 link	c.3373_3375delAAG	p.Lys1125del	conservative_inframe_deletion	Exon 25 of 29	1	NM_004672.5	ENSP00000350195.2		O95382-1

Frequencies

GnomAD3 genomes

AF:

0.00807

AC:

1229

AN:

152212

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00229

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00608

Gnomad ASJ

AF:

0.0110

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00166

Gnomad FIN

AF:

0.00942

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.0129

Gnomad OTH

AF:

0.00766

GnomAD2 exomes

AF:

0.00763

AC:

1596

AN:

209300

AF XY:

0.00799

show subpopulations

Gnomad AFR exome

AF:

0.00145

Gnomad AMR exome

AF:

0.00369

Gnomad ASJ exome

AF:

0.0130

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00696

Gnomad NFE exome

AF:

0.0123

Gnomad OTH exome

AF:

0.00709

GnomAD4 exome

AF:

0.0112

AC:

15821

AN:

1413666

Hom.:

123

AF XY:

0.0110

AC XY:

7703

AN XY:

698468

show subpopulations

African (AFR)

AF:

0.00169

AC:

AN:

32010

American (AMR)

AF:

0.00390

AC:

150

AN:

38462

Ashkenazi Jewish (ASJ)

AF:

0.0109

AC:

247

AN:

22676

East Asian (EAS)

AF:

0.0000255

AC:

AN:

39264

South Asian (SAS)

AF:

0.00241

AC:

190

AN:

78890

European-Finnish (FIN)

AF:

0.00701

AC:

363

AN:

51814

Middle Eastern (MID)

AF:

0.00582

AC:

AN:

4812

European-Non Finnish (NFE)

AF:

0.0131

AC:

14287

AN:

1087646

Other (OTH)

AF:

0.00862

AC:

501

AN:

58092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

854

1708

2562

3416

4270

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

542

1084

1626

2168

2710

<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:

0.00807

AC:

1229

AN:

152330

Hom.:

Cov.:

AF XY:

0.00772

AC XY:

575

AN XY:

74484

show subpopulations

African (AFR)

AF:

0.00229

AC:

AN:

41574

American (AMR)

AF:

0.00607

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.0110

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00166

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00942

AC:

100

AN:

10620

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0129

AC:

876

AN:

68036

Other (OTH)

AF:

0.00758

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

116

175

233

291

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00975

Hom.:

Bravo

AF:

0.00784

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Nov 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

MAP3K6: PM4:Supporting, BS1, BS2 -

MAP3K6-related disorder

Benign:1

Mar 26, 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

PhyloP100

0.22

Mutation Taster

=81/19

polymorphism

(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