rs832582

Variant names:

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.2716G>A(p.Val906Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.801 in 1,613,750 control chromosomes in the GnomAD database, including 520,423 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.77 ( 45806 hom., cov: 30)

Exomes 𝑓: 0.80 ( 474617 hom. )

Consequence

MAP3K1
NM_005921.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 1.45

Publications

87 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=7.638531E-7).

BP6

Variant 5-56881916-G-A is Benign according to our data. Variant chr5-56881916-G-A is described in ClinVar as Benign. ClinVar VariationId is 518365.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.815 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAP3K1	NM_005921.2 link	c.2716G>A	p.Val906Ile	missense_variant	Exon 14 of 20	ENST00000399503.4	NP_005912.1	Q13233
MAP3K1	XM_047417218.1 link	c.2716G>A	p.Val906Ile	missense_variant	Exon 14 of 18		XP_047273174.1
MAP3K1	XM_047417219.1 link	c.2305G>A	p.Val769Ile	missense_variant	Exon 15 of 21		XP_047273175.1
MAP3K1	XM_047417220.1 link	c.2305G>A	p.Val769Ile	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.2716G>A	p.Val906Ile	missense_variant	Exon 14 of 20	1	NM_005921.2	ENSP00000382423.3		Q13233

Frequencies

GnomAD3 genomes

AF:

0.773

AC:

117429

AN:

151824

Hom.:

45752

Cov.:

show subpopulations

Gnomad AFR

AF:

0.747

Gnomad AMI

AF:

0.712

Gnomad AMR

AF:

0.674

Gnomad ASJ

AF:

0.819

Gnomad EAS

AF:

0.578

Gnomad SAS

AF:

0.769

Gnomad FIN

AF:

0.809

Gnomad MID

AF:

0.706

Gnomad NFE

AF:

0.821

Gnomad OTH

AF:

0.774

GnomAD2 exomes

AF:

0.758

AC:

188624

AN:

248982

AF XY:

0.767

show subpopulations

Gnomad AFR exome

AF:

0.747

Gnomad AMR exome

AF:

0.591

Gnomad ASJ exome

AF:

0.821

Gnomad EAS exome

AF:

0.567

Gnomad FIN exome

AF:

0.806

Gnomad NFE exome

AF:

0.820

Gnomad OTH exome

AF:

0.771

GnomAD4 exome

AF:

0.803

AC:

1174502

AN:

1461808

Hom.:

474617

Cov.:

AF XY:

0.803

AC XY:

583889

AN XY:

727192

show subpopulations

African (AFR)

AF:

0.739

AC:

24751

AN:

33476

American (AMR)

AF:

0.600

AC:

26815

AN:

44698

Ashkenazi Jewish (ASJ)

AF:

0.825

AC:

21557

AN:

26136

East Asian (EAS)

AF:

0.569

AC:

22581

AN:

39694

South Asian (SAS)

AF:

0.778

AC:

67085

AN:

86254

European-Finnish (FIN)

AF:

0.807

AC:

43125

AN:

53416

Middle Eastern (MID)

AF:

0.783

AC:

4515

AN:

5768

European-Non Finnish (NFE)

AF:

0.824

AC:

916511

AN:

1111974

Other (OTH)

AF:

0.788

AC:

47562

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

14526

29053

43579

58106

72632

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

20924

41848

62772

83696

104620

<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:

0.774

AC:

117538

AN:

151942

Hom.:

45806

Cov.:

AF XY:

0.769

AC XY:

57084

AN XY:

74254

show subpopulations

African (AFR)

AF:

0.747

AC:

30915

AN:

41396

American (AMR)

AF:

0.674

AC:

10280

AN:

15262

Ashkenazi Jewish (ASJ)

AF:

0.819

AC:

2842

AN:

3472

East Asian (EAS)

AF:

0.579

AC:

2994

AN:

5174

South Asian (SAS)

AF:

0.769

AC:

3693

AN:

4802

European-Finnish (FIN)

AF:

0.809

AC:

8532

AN:

10548

Middle Eastern (MID)

AF:

0.711

AC:

209

AN:

294

European-Non Finnish (NFE)

AF:

0.821

AC:

55791

AN:

67978

Other (OTH)

AF:

0.776

AC:

1634

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1310

2620

3929

5239

6549

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

856

1712

2568

3424

4280

<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:

0.798

Hom.:

240578

Bravo

AF:

0.760

TwinsUK

AF:

0.828

AC:

3072

ALSPAC

AF:

0.826

AC:

3184

ESP6500AA

AF:

0.745

AC:

2819

ESP6500EA

AF:

0.823

AC:

6785

ExAC

AF:

0.764

AC:

92324

Asia WGS

AF:

0.697

AC:

2425

AN:

3478

EpiCase

AF:

0.815

EpiControl

AF:

0.817

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

46,XY sex reversal 6

Benign:3

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

- -

not provided

Benign:1

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

0.076

BayesDel_addAF

Benign

-0.81

BayesDel_noAF

Benign

-0.79

CADD

Benign

8.2

(source)

DANN

Benign

0.14

DEOGEN2

Benign

0.076

Eigen

Benign

-0.98

Eigen_PC

Benign

-0.90

FATHMM_MKL

Uncertain

0.77

LIST_S2

Benign

0.31

MetaRNN

Benign

7.6e-7

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.11

PhyloP100

1.4

PrimateAI

Benign

0.28

PROVEAN

Benign

0.11

REVEL

Benign

0.080

Sift

Benign

0.85

Sift4G

Benign

0.46

Polyphen

0.0

Vest4

0.0090

MPC

0.19

ClinPred

0.0037

GERP RS

3.6

Varity_R

0.024

gMVP

0.092

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