chr5-56815617-C-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2

The NM_005921.2(MAP3K1):c.44C>G(p.Pro15Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00012 in 1,312,112 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P15P) has been classified as Benign.

Frequency

Genomes: 𝑓 0.00012 ( 0 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: 3.56

Publications

2 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, Labcorp Genetics (formerly Invitae), G2P
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:

ENSG00000297204 (HGNC:):

ENSG00000297204 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.25606436).

BP6

Variant 5-56815617-C-G is Benign according to our data. Variant chr5-56815617-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1033045.

BS2

High AC in GnomAd4 at 18 AD gene.

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.44C>G	p.Pro15Arg	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.44C>G	p.Pro15Arg	missense	Exon 1 of 20	ENSP00000382423.3	Q13233
MAP3K1	ENST00000872825.1		c.44C>G	p.Pro15Arg	missense	Exon 1 of 20	ENSP00000542884.1
MAP3K1	ENST00000948659.1		c.44C>G	p.Pro15Arg	missense	Exon 1 of 19	ENSP00000618718.1

Frequencies

GnomAD3 genomes

AF:

0.000119

AC:

AN:

151212

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000208

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000236

Gnomad OTH

AF:

0.000480

GnomAD2 exomes

AF:

0.0000426

AC:

AN:

23490

AF XY:

0.0000681

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00175

GnomAD4 exome

AF:

0.000120

AC:

139

AN:

1160900

Hom.:

Cov.:

AF XY:

0.000126

AC XY:

AN XY:

563282

show subpopulations

African (AFR)

AF:

0.0000848

AC:

AN:

23596

American (AMR)

AF:

0.00

AC:

AN:

12310

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

16970

East Asian (EAS)

AF:

0.0000372

AC:

AN:

26868

South Asian (SAS)

AF:

0.0000698

AC:

AN:

42982

European-Finnish (FIN)

AF:

0.0000403

AC:

AN:

24784

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3198

European-Non Finnish (NFE)

AF:

0.000133

AC:

128

AN:

963764

Other (OTH)

AF:

0.0000862

AC:

AN:

46428

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

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:

0.000119

AC:

AN:

151212

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

AN XY:

73862

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41222

American (AMR)

AF:

0.00

AC:

AN:

15200

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3452

East Asian (EAS)

AF:

0.00

AC:

AN:

5100

South Asian (SAS)

AF:

0.000208

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10412

Middle Eastern (MID)

AF:

0.00

AC:

AN:

304

European-Non Finnish (NFE)

AF:

0.000236

AC:

AN:

67722

Other (OTH)

AF:

0.000480

AC:

AN:

2082

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.000142

Hom.:

Bravo

AF:

0.000121

ExAC

AF:

0.0000309

AC:

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

46,XY sex reversal 6 (2)

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Uncertain

0.026

BayesDel_noAF

Benign

-0.20

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.083

Eigen

Benign

0.060

Eigen_PC

Benign

0.11

FATHMM_MKL

Benign

0.078

LIST_S2

Benign

0.53

MetaRNN

Benign

0.26

MetaSVM

Benign

-0.80

MutationAssessor

Benign

0.55

PhyloP100

3.6

PrimateAI

Pathogenic

0.93

PROVEAN

Benign

-0.26

REVEL

Benign

0.10

Sift

Uncertain

0.014

Sift4G

Benign

0.10

Polyphen

0.93

Vest4

0.59

MutPred

0.31

Gain of MoRF binding (P = 9e-04)

MVP

0.57

MPC

0.79

ClinPred

0.22

GERP RS

3.1

PromoterAI

0.21

Neutral

(source)

Varity_R

0.22

gMVP

0.15

Mutation Taster

=87/13

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over