Genetic Variant NM_005921.2:c.65C>T (chr5-56815638-C-T) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4BS2

The NM_005921.2(MAP3K1):c.65C>T(p.Pro22Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000093 in 1,183,314 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000093 ( 0 hom. )

Consequence

MAP3K1
NM_005921.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.491

Publications

0 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, Labcorp Genetics (formerly Invitae), G2P
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:

ENSG00000297204 (HGNC:):

ENSG00000297204 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.40530574).

BS2

High AC in GnomAdExome4 at 11 AD gene.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAP3K1	NM_005921.2	MANE Select	c.65C>T	p.Pro22Leu	missense	Exon 1 of 20	NP_005912.1	Q13233

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MAP3K1	ENST00000399503.4	TSL:1 MANE Select	c.65C>T	p.Pro22Leu	missense	Exon 1 of 20	ENSP00000382423.3	Q13233
MAP3K1	ENST00000872825.1		c.65C>T	p.Pro22Leu	missense	Exon 1 of 20	ENSP00000542884.1
MAP3K1	ENST00000948659.1		c.65C>T	p.Pro22Leu	missense	Exon 1 of 19	ENSP00000618718.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000930

AC:

AN:

1183314

Hom.:

Cov.:

AF XY:

0.0000104

AC XY:

AN XY:

576508

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

24128

American (AMR)

AF:

0.00

AC:

AN:

14994

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18118

East Asian (EAS)

AF:

0.0000371

AC:

AN:

26978

South Asian (SAS)

AF:

0.00

AC:

AN:

47072

European-Finnish (FIN)

AF:

0.00

AC:

AN:

25626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3300

European-Non Finnish (NFE)

AF:

0.0000103

AC:

AN:

975534

Other (OTH)

AF:

0.00

AC:

AN:

47564

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000189

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Uncertain

0.042

BayesDel_noAF

Benign

-0.18

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.094

Eigen

Uncertain

0.24

Eigen_PC

Benign

0.19

FATHMM_MKL

Benign

0.23

LIST_S2

Benign

0.65

M_CAP

Pathogenic

0.95

MetaRNN

Benign

0.41

MetaSVM

Benign

-0.52

MutationAssessor

Benign

0.55

PhyloP100

0.49

PrimateAI

Pathogenic

0.93

PROVEAN

Benign

-0.70

REVEL

Benign

0.17

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.026

Polyphen

1.0

Vest4

0.40

MutPred

0.16

Loss of loop (P = 0.0112)

MVP

0.74

MPC

0.64

ClinPred

0.80

GERP RS

3.5

PromoterAI

-0.0044

Neutral

(source)

Varity_R

0.14

gMVP

0.091

Mutation Taster

=88/12

polymorphism

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over