rs702689

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

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

The NM_005921.2(MAP3K1):c.2416G>A(p.Asp806Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.671 in 1,612,860 control chromosomes in the GnomAD database, including 374,698 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.61 ( 29280 hom., cov: 31)

Exomes 𝑓: 0.68 ( 345418 hom. )

Consequence

MAP3K1
NM_005921.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 8.19

Publications

84 publications found

Variant links:

Genes affected

MAP3K1 (HGNC:6848): (mitogen-activated protein kinase kinase kinase 1) The protein encoded by this gene is a serine/threonine kinase and is part of some signal transduction cascades, including the ERK and JNK kinase pathways as well as the NF-kappa-B pathway. The encoded protein is activated by autophosphorylation and requires magnesium as a cofactor in phosphorylating other proteins. This protein has E3 ligase activity conferred by a plant homeodomain (PHD) in its N-terminus and phospho-kinase activity conferred by a kinase domain in its C-terminus. [provided by RefSeq, Mar 2012]

MAP3K1 Gene-Disease associations (from GenCC):

46,XY sex reversal 6
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
breast cancer
Inheritance: AD Classification: MODERATE Submitted by: G2P
46,XY complete gonadal dysgenesis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
46,XY partial gonadal dysgenesis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

MAP3K1 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=1.4606336E-5).

BP6

Variant 5-56881616-G-A is Benign according to our data. Variant chr5-56881616-G-A is described in ClinVar as Benign. ClinVar VariationId is 518364.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.71 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAP3K1	NM_005921.2 link	c.2416G>A	p.Asp806Asn	missense_variant	Exon 14 of 20	ENST00000399503.4	NP_005912.1	Q13233
MAP3K1	XM_047417218.1 link	c.2416G>A	p.Asp806Asn	missense_variant	Exon 14 of 18		XP_047273174.1
MAP3K1	XM_047417219.1 link	c.2005G>A	p.Asp669Asn	missense_variant	Exon 15 of 21		XP_047273175.1
MAP3K1	XM_047417220.1 link	c.2005G>A	p.Asp669Asn	missense_variant	Exon 15 of 21		XP_047273176.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAP3K1	ENST00000399503.4 link	c.2416G>A	p.Asp806Asn	missense_variant	Exon 14 of 20	1	NM_005921.2	ENSP00000382423.3		Q13233

Frequencies

GnomAD3 genomes

AF:

0.607

AC:

92147

AN:

151850

Hom.:

29262

Cov.:

show subpopulations

Gnomad AFR

AF:

0.489

Gnomad AMI

AF:

0.629

Gnomad AMR

AF:

0.498

Gnomad ASJ

AF:

0.721

Gnomad EAS

AF:

0.231

Gnomad SAS

AF:

0.481

Gnomad FIN

AF:

0.721

Gnomad MID

AF:

0.583

Gnomad NFE

AF:

0.716

Gnomad OTH

AF:

0.628

GnomAD2 exomes

AF:

0.594

AC:

147940

AN:

249066

AF XY:

0.603

show subpopulations

Gnomad AFR exome

AF:

0.490

Gnomad AMR exome

AF:

0.415

Gnomad ASJ exome

AF:

0.728

Gnomad EAS exome

AF:

0.206

Gnomad FIN exome

AF:

0.722

Gnomad NFE exome

AF:

0.712

Gnomad OTH exome

AF:

0.632

GnomAD4 exome

AF:

0.678

AC:

990820

AN:

1460892

Hom.:

345418

Cov.:

AF XY:

0.674

AC XY:

490099

AN XY:

726832

show subpopulations

African (AFR)

AF:

0.486

AC:

16252

AN:

33432

American (AMR)

AF:

0.425

AC:

19002

AN:

44702

Ashkenazi Jewish (ASJ)

AF:

0.729

AC:

19040

AN:

26130

East Asian (EAS)

AF:

0.236

AC:

9381

AN:

39694

South Asian (SAS)

AF:

0.505

AC:

43536

AN:

86234

European-Finnish (FIN)

AF:

0.719

AC:

38356

AN:

53356

Middle Eastern (MID)

AF:

0.653

AC:

3765

AN:

5764

European-Non Finnish (NFE)

AF:

0.722

AC:

802315

AN:

1111210

Other (OTH)

AF:

0.649

AC:

39173

AN:

60370

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

16428

32857

49285

65714

82142

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

19646

39292

58938

78584

98230

<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:

0.607

AC:

92200

AN:

151968

Hom.:

29280

Cov.:

AF XY:

0.600

AC XY:

44550

AN XY:

74300

show subpopulations

African (AFR)

AF:

0.490

AC:

20282

AN:

41420

American (AMR)

AF:

0.498

AC:

7586

AN:

15248

Ashkenazi Jewish (ASJ)

AF:

0.721

AC:

2502

AN:

3470

East Asian (EAS)

AF:

0.232

AC:

1195

AN:

5160

South Asian (SAS)

AF:

0.482

AC:

2318

AN:

4812

European-Finnish (FIN)

AF:

0.721

AC:

7622

AN:

10570

Middle Eastern (MID)

AF:

0.582

AC:

170

AN:

292

European-Non Finnish (NFE)

AF:

0.716

AC:

48633

AN:

67970

Other (OTH)

AF:

0.623

AC:

1318

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1725

3450

5176

6901

8626

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

748

1496

2244

2992

3740

<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:

0.671

Hom.:

174650

Bravo

AF:

0.585

TwinsUK

AF:

0.724

AC:

2684

ALSPAC

AF:

0.722

AC:

2782

ESP6500AA

AF:

0.495

AC:

1844

ESP6500EA

AF:

0.721

AC:

5908

ExAC

AF:

0.598

AC:

72226

Asia WGS

AF:

0.379

AC:

1319

AN:

3478

EpiCase

AF:

0.711

EpiControl

AF:

0.710

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

46,XY sex reversal 6

Benign:3

Nov 02, 2017

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:2

Nov 12, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 22468730, 24497709) -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.52

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.069

Eigen

Pathogenic

0.68

Eigen_PC

Pathogenic

0.72

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.95

MetaRNN

Benign

0.000015

MetaSVM

Benign

-0.98

MutationAssessor

Uncertain

2.1

PhyloP100

8.2

PrimateAI

Uncertain

0.69

PROVEAN

Benign

-0.10

REVEL

Benign

0.15

Sift

Benign

0.20

Sift4G

Benign

0.65

Polyphen

1.0

Vest4

0.33

MPC

0.26

ClinPred

0.044

GERP RS

5.6

Varity_R

0.37

gMVP

0.46

Mutation Taster

=83/17

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