5-56859845-A-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.764A>G(p.Asn255Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0255 in 1,613,710 control chromosomes in the GnomAD database, including 551 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.024 ( 42 hom., cov: 32)

Exomes 𝑓: 0.026 ( 509 hom. )

Consequence

MAP3K1
NM_005921.2 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 3.06

Publications

24 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:

ENSG00000237705 (HGNC:):

ENSG00000237705 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=0.0015856028).

BP6

Variant 5-56859845-A-G is Benign according to our data. Variant chr5-56859845-A-G is described in ClinVar as Benign. ClinVar VariationId is 471695.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0239 (3641/152232) while in subpopulation NFE AF = 0.028 (1905/68004). AF 95% confidence interval is 0.027. There are 42 homozygotes in GnomAd4. There are 1773 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 3641 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAP3K1	NM_005921.2 link	c.764A>G	p.Asn255Ser	missense_variant	Exon 3 of 20	ENST00000399503.4	NP_005912.1	Q13233
MAP3K1	XM_047417218.1 link	c.764A>G	p.Asn255Ser	missense_variant	Exon 3 of 18		XP_047273174.1
MAP3K1	XM_047417219.1 link	c.353A>G	p.Asn118Ser	missense_variant	Exon 4 of 21		XP_047273175.1
MAP3K1	XM_047417220.1 link	c.353A>G	p.Asn118Ser	missense_variant	Exon 4 of 21		XP_047273176.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAP3K1	ENST00000399503.4 link	c.764A>G	p.Asn255Ser	missense_variant	Exon 3 of 20	1	NM_005921.2	ENSP00000382423.3		Q13233
ENSG00000237705	ENST00000415589.1 link	n.160T>C		non_coding_transcript_exon_variant	Exon 2 of 4	3

Frequencies

GnomAD3 genomes

AF:

0.0239

AC:

3643

AN:

152114

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0219

Gnomad AMI

AF:

0.0735

Gnomad AMR

AF:

0.0206

Gnomad ASJ

AF:

0.0124

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00249

Gnomad FIN

AF:

0.0311

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.0280

Gnomad OTH

AF:

0.0292

GnomAD2 exomes

AF:

0.0195

AC:

4839

AN:

248550

AF XY:

0.0192

show subpopulations

Gnomad AFR exome

AF:

0.0221

Gnomad AMR exome

AF:

0.0141

Gnomad ASJ exome

AF:

0.0148

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0266

Gnomad NFE exome

AF:

0.0273

Gnomad OTH exome

AF:

0.0194

GnomAD4 exome

AF:

0.0257

AC:

37547

AN:

1461478

Hom.:

509

Cov.:

AF XY:

0.0252

AC XY:

18310

AN XY:

726998

show subpopulations

African (AFR)

AF:

0.0224

AC:

749

AN:

33478

American (AMR)

AF:

0.0155

AC:

693

AN:

44706

Ashkenazi Jewish (ASJ)

AF:

0.0150

AC:

393

AN:

26130

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39656

South Asian (SAS)

AF:

0.00323

AC:

278

AN:

86164

European-Finnish (FIN)

AF:

0.0249

AC:

1331

AN:

53376

Middle Eastern (MID)

AF:

0.0125

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.0293

AC:

32571

AN:

1111820

Other (OTH)

AF:

0.0242

AC:

1459

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.456

Heterozygous variant carriers

1899

3798

5697

7596

9495

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1192

2384

3576

4768

5960

<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:

0.0239

AC:

3641

AN:

152232

Hom.:

Cov.:

AF XY:

0.0238

AC XY:

1773

AN XY:

74444

show subpopulations

African (AFR)

AF:

0.0218

AC:

907

AN:

41528

American (AMR)

AF:

0.0205

AC:

314

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.0124

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00249

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.0311

AC:

330

AN:

10606

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0280

AC:

1905

AN:

68004

Other (OTH)

AF:

0.0289

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

187

374

560

747

934

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

126

168

210

<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:

0.0263

Hom.:

113

Bravo

AF:

0.0241

TwinsUK

AF:

0.0283

AC:

105

ALSPAC

AF:

0.0293

AC:

113

ESP6500AA

AF:

0.0206

AC:

ESP6500EA

AF:

0.0277

AC:

229

ExAC

AF:

0.0195

AC:

2353

Asia WGS

AF:

0.00433

AC:

AN:

3478

EpiCase

AF:

0.0305

EpiControl

AF:

0.0282

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

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

- -

Apr 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

MAP3K1: BP4, BS1, BS2 -

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

Jan 29, 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

0.044

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.61

CADD

Benign

(source)

DANN

Benign

0.68

DEOGEN2

Benign

0.074

Eigen

Benign

-0.80

Eigen_PC

Benign

-0.53

FATHMM_MKL

Benign

0.25

LIST_S2

Benign

0.68

MetaRNN

Benign

0.0016

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-1.0

PhyloP100

3.1

PrimateAI

Benign

0.31

PROVEAN

Benign

0.22

REVEL

Benign

0.088

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.044

MPC

0.18

ClinPred

0.0036

GERP RS

3.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.035

gMVP

0.18

Mutation Taster

=98/2

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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