NM_005921.2:c.1566C>T

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.1566C>T(p.Thr522Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0529 in 1,613,946 control chromosomes in the GnomAD database, including 2,428 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.044 ( 158 hom., cov: 32)

Exomes 𝑓: 0.054 ( 2270 hom. )

Consequence

MAP3K1
NM_005921.2 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.0540

Publications

27 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=-0.78).

BP6

Variant 5-56872885-C-T is Benign according to our data. Variant chr5-56872885-C-T is described in ClinVar as Benign. ClinVar VariationId is 471689.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.054 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0558 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAP3K1	NM_005921.2 link	c.1566C>T	p.Thr522Thr	synonymous_variant	Exon 9 of 20	ENST00000399503.4	NP_005912.1	Q13233
MAP3K1	XM_047417218.1 link	c.1566C>T	p.Thr522Thr	synonymous_variant	Exon 9 of 18		XP_047273174.1
MAP3K1	XM_047417219.1 link	c.1155C>T	p.Thr385Thr	synonymous_variant	Exon 10 of 21		XP_047273175.1
MAP3K1	XM_047417220.1 link	c.1155C>T	p.Thr385Thr	synonymous_variant	Exon 10 of 21		XP_047273176.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAP3K1	ENST00000399503.4 link	c.1566C>T	p.Thr522Thr	synonymous_variant	Exon 9 of 20	1	NM_005921.2	ENSP00000382423.3		Q13233

Frequencies

GnomAD3 genomes

AF:

0.0442

AC:

6728

AN:

152170

Hom.:

158

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0322

Gnomad AMI

AF:

0.0285

Gnomad AMR

AF:

0.0506

Gnomad ASJ

AF:

0.0579

Gnomad EAS

AF:

0.0610

Gnomad SAS

AF:

0.0308

Gnomad FIN

AF:

0.0275

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.0518

Gnomad OTH

AF:

0.0497

GnomAD2 exomes

AF:

0.0483

AC:

12045

AN:

249186

AF XY:

0.0472

show subpopulations

Gnomad AFR exome

AF:

0.0302

Gnomad AMR exome

AF:

0.0682

Gnomad ASJ exome

AF:

0.0586

Gnomad EAS exome

AF:

0.0557

Gnomad FIN exome

AF:

0.0273

Gnomad NFE exome

AF:

0.0527

Gnomad OTH exome

AF:

0.0461

GnomAD4 exome

AF:

0.0538

AC:

78683

AN:

1461658

Hom.:

2270

Cov.:

AF XY:

0.0531

AC XY:

38640

AN XY:

727124

show subpopulations

African (AFR)

AF:

0.0317

AC:

1061

AN:

33478

American (AMR)

AF:

0.0683

AC:

3055

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.0584

AC:

1527

AN:

26134

East Asian (EAS)

AF:

0.0658

AC:

2610

AN:

39686

South Asian (SAS)

AF:

0.0281

AC:

2426

AN:

86252

European-Finnish (FIN)

AF:

0.0290

AC:

1551

AN:

53410

Middle Eastern (MID)

AF:

0.0271

AC:

156

AN:

5766

European-Non Finnish (NFE)

AF:

0.0569

AC:

63248

AN:

1111830

Other (OTH)

AF:

0.0505

AC:

3049

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

3850

7700

11550

15400

19250

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2448

4896

7344

9792

12240

<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:

0.0442

AC:

6728

AN:

152288

Hom.:

158

Cov.:

AF XY:

0.0430

AC XY:

3206

AN XY:

74472

show subpopulations

African (AFR)

AF:

0.0321

AC:

1335

AN:

41552

American (AMR)

AF:

0.0505

AC:

773

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.0579

AC:

201

AN:

3472

East Asian (EAS)

AF:

0.0613

AC:

318

AN:

5188

South Asian (SAS)

AF:

0.0304

AC:

147

AN:

4828

European-Finnish (FIN)

AF:

0.0275

AC:

292

AN:

10604

Middle Eastern (MID)

AF:

0.0204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0518

AC:

3526

AN:

68026

Other (OTH)

AF:

0.0491

AC:

104

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

331

663

994

1326

1657

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

160

240

320

400

<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:

0.0502

Hom.:

420

Bravo

AF:

0.0473

Asia WGS

AF:

0.0400

AC:

139

AN:

3478

EpiCase

AF:

0.0522

EpiControl

AF:

0.0579

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

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

- -

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

BayesDel_noAF

Benign

-0.78

CADD

Benign

4.1

(source)

DANN

Benign

0.33

PhyloP100

0.054

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over