Genetic Variant MAP3K1:p.Thr949dup (chr5-56882021-T-TCAA) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP6_ModerateBS2

The NM_005921.2(MAP3K1):c.2845_2847dupACA(p.Thr949dup) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.00075 ( 0 hom., cov: 0)

Exomes 𝑓: 0.00085 ( 1 hom. )

Consequence

MAP3K1
NM_005921.2 conservative_inframe_insertion

Scores

Not classified

Clinical Significance

Likely benign criteria provided, single submitter B:2

Conservation

PhyloP100: 3.28

Publications

23 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: Likely_benign. The variant received -6 ACMG points.

BP6

Variant 5-56882021-T-TCAA is Benign according to our data. Variant chr5-56882021-T-TCAA is described in ClinVar as Likely_benign. ClinVar VariationId is 1954893.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High AC in GnomAd4 at 113 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAP3K1	NM_005921.2 link	c.2845_2847dupACA	p.Thr949dup	conservative_inframe_insertion	Exon 14 of 20	ENST00000399503.4	NP_005912.1	Q13233
MAP3K1	XM_047417218.1 link	c.2845_2847dupACA	p.Thr949dup	conservative_inframe_insertion	Exon 14 of 18		XP_047273174.1
MAP3K1	XM_047417219.1 link	c.2434_2436dupACA	p.Thr812dup	conservative_inframe_insertion	Exon 15 of 21		XP_047273175.1
MAP3K1	XM_047417220.1 link	c.2434_2436dupACA	p.Thr812dup	conservative_inframe_insertion	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.2845_2847dupACA	p.Thr949dup	conservative_inframe_insertion	Exon 14 of 20	1	NM_005921.2	ENSP00000382423.3		Q13233

Frequencies

GnomAD3 genomes

AF:

0.000749

AC:

113

AN:

150946

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000366

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00191

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000781

Gnomad SAS

AF:

0.000833

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000856

Gnomad OTH

AF:

0.00145

GnomAD2 exomes

AF:

0.000597

AC:

137

AN:

229430

AF XY:

0.000557

show subpopulations

Gnomad AFR exome

AF:

0.000693

Gnomad AMR exome

AF:

0.000923

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000996

Gnomad FIN exome

AF:

0.0000508

Gnomad NFE exome

AF:

0.000680

Gnomad OTH exome

AF:

0.000358

GnomAD4 exome

AF:

0.000852

AC:

1211

AN:

1421414

Hom.:

Cov.:

AF XY:

0.000824

AC XY:

583

AN XY:

707620

show subpopulations

African (AFR)

AF:

0.000610

AC:

AN:

32802

American (AMR)

AF:

0.000929

AC:

AN:

44156

Ashkenazi Jewish (ASJ)

AF:

0.0000784

AC:

AN:

25526

East Asian (EAS)

AF:

0.000584

AC:

AN:

39394

South Asian (SAS)

AF:

0.000249

AC:

AN:

84488

European-Finnish (FIN)

AF:

0.0000191

AC:

AN:

52274

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5658

European-Non Finnish (NFE)

AF:

0.000965

AC:

1040

AN:

1078188

Other (OTH)

AF:

0.00107

AC:

AN:

58928

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

149

223

298

372

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

138

184

230

<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:

0.000748

AC:

113

AN:

151064

Hom.:

Cov.:

AF XY:

0.000651

AC XY:

AN XY:

73744

show subpopulations

African (AFR)

AF:

0.000365

AC:

AN:

41068

American (AMR)

AF:

0.00191

AC:

AN:

15180

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3462

East Asian (EAS)

AF:

0.000782

AC:

AN:

5112

South Asian (SAS)

AF:

0.000834

AC:

AN:

4796

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10412

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.000856

AC:

AN:

67742

Other (OTH)

AF:

0.00143

AC:

AN:

2098

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

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:

0.000428

Hom.:

4880

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

MAP3K1-related disorder

Benign:1

Dec 19, 2019

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

46,XY sex reversal 6

Benign:1

Jun 11, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

3.3

Mutation Taster

=66/34

polymorphism

(source)

Splicing

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