chr5-56882016-C-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_005921.2(MAP3K1):c.2816C>G(p.Ser939Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0206 in 1,544,892 control chromosomes in the GnomAD database, including 402 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 0.028 ( 35 hom., cov: 31)

Exomes 𝑓: 0.020 ( 367 hom. )

Consequence

MAP3K1
NM_005921.2 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 2.11

Publications

28 publications found

Variant links:

COSMIC-nc: COSV68127595

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=0.0024033189).

BP6

Variant 5-56882016-C-G is Benign according to our data. Variant chr5-56882016-C-G is described in ClinVar as Benign. ClinVar VariationId is 471692.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.028 (2324/83092) while in subpopulation AMR AF = 0.0418 (401/9598). AF 95% confidence interval is 0.0389. There are 35 homozygotes in GnomAd4. There are 1062 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High AC in GnomAd4 at 2324 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAP3K1	NM_005921.2 link	c.2816C>G	p.Ser939Cys	missense_variant	Exon 14 of 20	ENST00000399503.4	NP_005912.1	Q13233
MAP3K1	XM_047417218.1 link	c.2816C>G	p.Ser939Cys	missense_variant	Exon 14 of 18		XP_047273174.1
MAP3K1	XM_047417219.1 link	c.2405C>G	p.Ser802Cys	missense_variant	Exon 15 of 21		XP_047273175.1
MAP3K1	XM_047417220.1 link	c.2405C>G	p.Ser802Cys	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.2816C>G	p.Ser939Cys	missense_variant	Exon 14 of 20	1	NM_005921.2	ENSP00000382423.3		Q13233

Frequencies

GnomAD3 genomes

AF:

0.0280

AC:

2326

AN:

83008

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00799

Gnomad AMI

AF:

0.00484

Gnomad AMR

AF:

0.0420

Gnomad ASJ

AF:

0.0866

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0115

Gnomad FIN

AF:

0.00585

Gnomad MID

AF:

0.0327

Gnomad NFE

AF:

0.0406

Gnomad OTH

AF:

0.0421

GnomAD2 exomes

AF:

0.0158

AC:

3907

AN:

247510

AF XY:

0.0160

show subpopulations

Gnomad AFR exome

AF:

0.00404

Gnomad AMR exome

AF:

0.0186

Gnomad ASJ exome

AF:

0.0435

Gnomad EAS exome

AF:

0.000111

Gnomad FIN exome

AF:

0.00331

Gnomad NFE exome

AF:

0.0214

Gnomad OTH exome

AF:

0.0225

GnomAD4 exome

AF:

0.0202

AC:

29477

AN:

1461800

Hom.:

367

Cov.:

AF XY:

0.0196

AC XY:

14265

AN XY:

727196

show subpopulations

African (AFR)

AF:

0.00364

AC:

122

AN:

33478

American (AMR)

AF:

0.0189

AC:

847

AN:

44704

Ashkenazi Jewish (ASJ)

AF:

0.0475

AC:

1242

AN:

26136

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39694

South Asian (SAS)

AF:

0.00585

AC:

505

AN:

86256

European-Finnish (FIN)

AF:

0.00386

AC:

206

AN:

53412

Middle Eastern (MID)

AF:

0.0385

AC:

222

AN:

5768

European-Non Finnish (NFE)

AF:

0.0225

AC:

25048

AN:

1111962

Other (OTH)

AF:

0.0212

AC:

1283

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

1770

3539

5309

7078

8848

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

944

1888

2832

3776

4720

<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:

0.0280

AC:

2324

AN:

83092

Hom.:

Cov.:

AF XY:

0.0262

AC XY:

1062

AN XY:

40532

show subpopulations

African (AFR)

AF:

0.00791

AC:

178

AN:

22492

American (AMR)

AF:

0.0418

AC:

401

AN:

9598

Ashkenazi Jewish (ASJ)

AF:

0.0866

AC:

171

AN:

1974

East Asian (EAS)

AF:

0.00

AC:

AN:

3834

South Asian (SAS)

AF:

0.0124

AC:

AN:

2348

European-Finnish (FIN)

AF:

0.00585

AC:

AN:

4956

Middle Eastern (MID)

AF:

0.0303

AC:

AN:

198

European-Non Finnish (NFE)

AF:

0.0406

AC:

1460

AN:

35942

Other (OTH)

AF:

0.0416

AC:

AN:

1130

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

124

248

373

497

621

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

104

130

<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:

0.0228

Hom.:

Bravo

AF:

0.0165

ESP6500AA

AF:

0.00525

AC:

ESP6500EA

AF:

0.0231

AC:

191

ExAC

AF:

0.0150

AC:

1816

EpiCase

AF:

0.0255

EpiControl

AF:

0.0278

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Jan 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

MAP3K1: BP4, BS1, BS2 -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not specified

Benign:1

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

46,XY sex reversal 6

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.078

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.60

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.076

Eigen

Benign

-0.20

Eigen_PC

Benign

-0.012

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.63

MetaRNN

Benign

0.0024

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

PhyloP100

2.1

PrimateAI

Benign

0.31

PROVEAN

Benign

-0.13

REVEL

Benign

0.033

Sift

Uncertain

0.0020

Sift4G

Benign

0.11

Polyphen

0.10

Vest4

0.065

MPC

0.23

ClinPred

0.018

GERP RS

3.9

Varity_R

0.13

gMVP

0.12

Mutation Taster

=94/6

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