NM_005921.2:c.3084A>G

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_005921.2(MAP3K1):c.3084A>G(p.Gln1028Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0732 in 1,614,018 control chromosomes in the GnomAD database, including 4,573 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.079 ( 502 hom., cov: 32)

Exomes 𝑓: 0.073 ( 4071 hom. )

Consequence

MAP3K1
NM_005921.2 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 1.39

Publications

26 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.56).

BP6

Variant 5-56882284-A-G is Benign according to our data. Variant chr5-56882284-A-G is described in ClinVar as Benign. ClinVar VariationId is 1170263.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=1.39 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.11 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAP3K1	NM_005921.2	MANE Select	c.3084A>G	p.Gln1028Gln	synonymous	Exon 14 of 20	NP_005912.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAP3K1	ENST00000399503.4	TSL:1 MANE Select	c.3084A>G	p.Gln1028Gln	synonymous	Exon 14 of 20	ENSP00000382423.3

Frequencies

GnomAD3 genomes

AF:

0.0789

AC:

11993

AN:

152080

Hom.:

499

Cov.:

show subpopulations

Gnomad AFR

AF:

0.104

Gnomad AMI

AF:

0.0461

Gnomad AMR

AF:

0.0670

Gnomad ASJ

AF:

0.0677

Gnomad EAS

AF:

0.117

Gnomad SAS

AF:

0.0571

Gnomad FIN

AF:

0.0740

Gnomad MID

AF:

0.0411

Gnomad NFE

AF:

0.0667

Gnomad OTH

AF:

0.0822

GnomAD2 exomes

AF:

0.0720

AC:

17926

AN:

248996

AF XY:

0.0705

show subpopulations

Gnomad AFR exome

AF:

0.105

Gnomad AMR exome

AF:

0.0759

Gnomad ASJ exome

AF:

0.0725

Gnomad EAS exome

AF:

0.104

Gnomad FIN exome

AF:

0.0725

Gnomad NFE exome

AF:

0.0669

Gnomad OTH exome

AF:

0.0659

GnomAD4 exome

AF:

0.0726

AC:

106135

AN:

1461820

Hom.:

4071

Cov.:

AF XY:

0.0721

AC XY:

52449

AN XY:

727204

show subpopulations

African (AFR)

AF:

0.104

AC:

3477

AN:

33480

American (AMR)

AF:

0.0763

AC:

3412

AN:

44706

Ashkenazi Jewish (ASJ)

AF:

0.0699

AC:

1828

AN:

26136

East Asian (EAS)

AF:

0.139

AC:

5514

AN:

39696

South Asian (SAS)

AF:

0.0537

AC:

4635

AN:

86258

European-Finnish (FIN)

AF:

0.0740

AC:

3949

AN:

53398

Middle Eastern (MID)

AF:

0.0498

AC:

287

AN:

5768

European-Non Finnish (NFE)

AF:

0.0707

AC:

78660

AN:

1111984

Other (OTH)

AF:

0.0724

AC:

4373

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

5795

11589

17384

23178

28973

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3086

6172

9258

12344

15430

<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:

0.0789

AC:

12004

AN:

152198

Hom.:

502

Cov.:

AF XY:

0.0786

AC XY:

5850

AN XY:

74410

show subpopulations

African (AFR)

AF:

0.104

AC:

4325

AN:

41512

American (AMR)

AF:

0.0668

AC:

1022

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.0677

AC:

235

AN:

3470

East Asian (EAS)

AF:

0.117

AC:

607

AN:

5170

South Asian (SAS)

AF:

0.0565

AC:

273

AN:

4830

European-Finnish (FIN)

AF:

0.0740

AC:

784

AN:

10598

Middle Eastern (MID)

AF:

0.0374

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0667

AC:

4533

AN:

68010

Other (OTH)

AF:

0.0814

AC:

172

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

562

1124

1685

2247

2809

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

138

276

414

552

690

<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:

0.0702

Hom.:

1275

Bravo

AF:

0.0814

Asia WGS

AF:

0.0810

AC:

281

AN:

3478

EpiCase

AF:

0.0669

EpiControl

AF:

0.0689

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

46,XY sex reversal 6

Benign:2

Jun 24, 2022

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Benign. Following criteria are met: 0101 - Gain of function is a known mechanism of disease in this gene and is associated with 46XY sex reversal 6 (MIM#613762) (PMIDs: 24135036, 21129722, 30608580). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Intrafamilial and interfamilial variability have been reported, ranging from hypospadias to complete gonadal dysgenesis (PMIDs: 27899157, 12476449, 21129722). (I) 0212 - Non-canonical splice site variant without proven consequence on splicing (no functional evidence available). (I) 0251 - This variant is heterozygous. (I) 0308 - Population frequency for this variant is out of keeping with known incidence of 46XY sex reversal 6 (MIM#613762) (gnomAD v2: 18666 heterozygotes, 807 homozygotes). (SB) 0508 - In silico predictions for abnormal splicing are conflicting. (I) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0705 - No comparable single nucleotide substitution variants have previous evidence for pathogenicity. (I) 0806 - This variant has moderate previous evidence of being benign in unrelated individuals. It has been reported as benign by clinical testing laboratories (ClinVar). It has also been reported in one unrelated patient with 46,XY disorder of sex development, however there was no convincing evidence for its pathogenicity (PMIDs: 24497709, 28504475). (SB) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Nov 12, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.56

CADD

Benign

5.1

(source)

DANN

Benign

0.56

PhyloP100

1.4

Mutation Taster

=100/0

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over