Genetic Variant MAP3K1:p.Glu46Asp (chr5-56815711-G-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_005921.2(MAP3K1):c.138G>T(p.Glu46Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. E46E) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

MAP3K1
NM_005921.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.293

Publications

0 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.11764568).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005921.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAP3K1	NM_005921.2	MANE Select	c.138G>T	p.Glu46Asp	missense	Exon 1 of 20	NP_005912.1	Q13233

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MAP3K1	ENST00000399503.4	TSL:1 MANE Select	c.138G>T	p.Glu46Asp	missense	Exon 1 of 20	ENSP00000382423.3	Q13233
MAP3K1	ENST00000872825.1		c.138G>T	p.Glu46Asp	missense	Exon 1 of 20	ENSP00000542884.1
MAP3K1	ENST00000948659.1		c.138G>T	p.Glu46Asp	missense	Exon 1 of 19	ENSP00000618718.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1171624

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

569620

African (AFR)

AF:

0.00

AC:

AN:

24404

American (AMR)

AF:

0.00

AC:

AN:

15564

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

17492

East Asian (EAS)

AF:

0.00

AC:

AN:

26484

South Asian (SAS)

AF:

0.00

AC:

AN:

41118

European-Finnish (FIN)

AF:

0.00

AC:

AN:

25536

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3330

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

970326

Other (OTH)

AF:

0.00

AC:

AN:

47370

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

46,XY sex reversal 6 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.064

BayesDel_addAF

Benign

-0.10

BayesDel_noAF

Benign

-0.38

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.078

Eigen

Benign

-0.47

Eigen_PC

Benign

-0.34

FATHMM_MKL

Benign

0.18

LIST_S2

Benign

0.50

M_CAP

Pathogenic

0.47

MetaRNN

Benign

0.12

MetaSVM

Benign

-0.95

MutationAssessor

Benign

0.34

PhyloP100

0.29

PrimateAI

Pathogenic

0.92

PROVEAN

Benign

-0.13

REVEL

Benign

0.087

Sift

Uncertain

0.022

Sift4G

Benign

0.38

Polyphen

0.0040

Vest4

0.054

MutPred

0.11

Loss of helix (P = 0.0376)

MVP

0.50

MPC

0.30

ClinPred

0.22

GERP RS

2.8

PromoterAI

-0.13

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.5

Varity_R

0.22

gMVP

0.055

Mutation Taster

=94/6

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over