Genetic Variant MAP3K21:p.Ser597Cys (chr1-233376030-C-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_032435.3(MAP3K21):c.1790C>G(p.Ser597Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,166 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S597F) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Consequence

MAP3K21
NM_032435.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.49

Publications

10 publications found

Variant links:

Genes affected

MAP3K21 (HGNC:29798): (mitogen-activated protein kinase kinase kinase 21) Predicted to enable protein homodimerization activity and protein kinase activity. Predicted to be involved in protein autophosphorylation and signal transduction. Predicted to be active in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

MAP3K21 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032435.3. 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
	MAP3K21	NM_032435.3	MANE Select	c.1790C>G	p.Ser597Cys	missense	Exon 7 of 10	NP_115811.2	Q5TCX8-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MAP3K21	ENST00000366624.8	TSL:1 MANE Select	c.1790C>G	p.Ser597Cys	missense	Exon 7 of 10	ENSP00000355583.3	Q5TCX8-1
MAP3K21	ENST00000366622.1	TSL:1	c.128C>G	p.Ser43Cys	missense	Exon 1 of 4	ENSP00000355581.1	Q5TCX8-3
MAP3K21	ENST00000915953.1		c.1790C>G	p.Ser597Cys	missense	Exon 7 of 10	ENSP00000586012.1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152166

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152166

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74332

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

41442

American (AMR)

AF:

0.00

AC:

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000192

AC:

AN:

5196

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68030

Other (OTH)

AF:

0.00

AC:

AN:

2094

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

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:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

0.0092

BayesDel_noAF

Benign

-0.22

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.055

Eigen

Pathogenic

0.79

Eigen_PC

Pathogenic

0.75

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.86

M_CAP

Benign

0.018

MetaRNN

Uncertain

0.67

MetaSVM

Benign

-1.0

PhyloP100

7.5

PrimateAI

Benign

0.47

PROVEAN

Uncertain

-3.9

REVEL

Uncertain

0.31

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0040

Polyphen

1.0

Vest4

0.78

MutPred

0.32

Loss of disorder (P = 0.0424)

MVP

0.34

MPC

0.52

ClinPred

0.99

GERP RS

5.3

PromoterAI

0.060

Neutral

(source)

Varity_R

0.43

gMVP

0.57

Mutation Taster

=61/39

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

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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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over