5-56816031-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_005921.2(MAP3K1):c.458C>T(p.Pro153Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00013 in 1,222,046 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P153Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00022 ( 1 hom., cov: 33)

Exomes 𝑓: 0.00012 ( 0 hom. )

Consequence

MAP3K1
NM_005921.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: -1.28

Publications

3 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 -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.007707894).

BP6

Variant 5-56816031-C-T is Benign according to our data. Variant chr5-56816031-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 435820.

BS2

High AC in GnomAd4 at 34 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAP3K1	NM_005921.2 link	c.458C>T	p.Pro153Leu	missense_variant	Exon 1 of 20	ENST00000399503.4	NP_005912.1	Q13233
MAP3K1	XM_047417218.1 link	c.458C>T	p.Pro153Leu	missense_variant	Exon 1 of 18		XP_047273174.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAP3K1	ENST00000399503.4 link	c.458C>T	p.Pro153Leu	missense_variant	Exon 1 of 20	1	NM_005921.2	ENSP00000382423.3		Q13233

Frequencies

GnomAD3 genomes

AF:

0.000224

AC:

AN:

151732

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00662

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00

AC:

AN:

146

AF XY:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000117

AC:

125

AN:

1070204

Hom.:

Cov.:

AF XY:

0.000136

AC XY:

AN XY:

507426

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

22164

American (AMR)

AF:

0.00

AC:

AN:

7776

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

13434

East Asian (EAS)

AF:

0.00

AC:

AN:

25212

South Asian (SAS)

AF:

0.00446

AC:

AN:

19938

European-Finnish (FIN)

AF:

0.00

AC:

AN:

20886

Middle Eastern (MID)

AF:

0.000354

AC:

AN:

2824

European-Non Finnish (NFE)

AF:

0.0000153

AC:

AN:

915532

Other (OTH)

AF:

0.000495

AC:

AN:

42438

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.000224

AC:

AN:

151842

Hom.:

Cov.:

AF XY:

0.000391

AC XY:

AN XY:

74230

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41502

American (AMR)

AF:

0.00

AC:

AN:

15264

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5116

South Asian (SAS)

AF:

0.00662

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10456

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

67890

Other (OTH)

AF:

0.00

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.512

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.00

Hom.:

Bravo

AF:

0.0000567

ExAC

AF:

0.000516

AC:

Asia WGS

AF:

0.00636

AC:

AN:

3472

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

46,XY sex reversal 6

Uncertain:1

Mar 13, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 153 of the MAP3K1 protein (p.Pro153Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with gonadal dysplasia (PMID: 24135036; Invitae). ClinVar contains an entry for this variant (Variation ID: 435820). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt MAP3K1 protein function with a negative predictive value of 95%. Experimental studies have shown that this missense change affects MAP3K1 function (PMID: 24135036, 30608580). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not provided

Uncertain:1

May 16, 2018

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The P153L variant in the MAP3K1 gene has been reported previously in an individual with abnormal gonadal development with no further clinical details provided (Loke et al., 2014). Functional studies of this variant demonstrated altered binding of protein co-factors and increased phosphorylation of downstream targets, suggesting a possible gain of function (Loke et al., 2014). However, the clinical validity of these functional studies is unknown (Bashamboo et al., 2015). The P153L variant is not observed in large population cohorts (Lek et al., 2016). The P153L variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. However, in-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. We interpret P153L as a variant of uncertain significance. -

not specified

Benign:1

Jan 05, 2017

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.52

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.074

Eigen

Benign

-0.89

Eigen_PC

Benign

-0.88

FATHMM_MKL

Benign

0.0066

LIST_S2

Benign

0.51

M_CAP

Pathogenic

0.84

MetaRNN

Benign

0.0077

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.34

PhyloP100

-1.3

PrimateAI

Pathogenic

0.82

PROVEAN

Benign

0.11

REVEL

Uncertain

0.64

Sift

Uncertain

0.012

Sift4G

Benign

0.83

Polyphen

0.0

Vest4

0.061

MutPred

0.14

Loss of glycosylation at P153 (P = 0.0283);

MVP

0.51

MPC

0.23

ClinPred

0.12

GERP RS

-0.43

PromoterAI

-0.043

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.079

gMVP

0.19

Mutation Taster

=39/61

disease causing

(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