dbSNP rs746487486: MAP3K12:p.Ser728Phe (chr12-53482620-G-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001193511.2(MAP3K12):c.2183C>T(p.Ser728Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S728C) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

MAP3K12
NM_001193511.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.607

Publications

0 publications found

Variant links:

Genes affected

MAP3K12 (HGNC:6851): (mitogen-activated protein kinase kinase kinase 12) This gene encodes a member of the serine/threonine protein kinase family. This kinase contains a leucine-zipper domain and is predominately expressed in neuronal cells. The phosphorylation state of this kinase in synaptic terminals was shown to be regulated by membrane depolarization via calcineurin. This kinase forms heterodimers with leucine zipper containing transcription factors, such as cAMP responsive element binding protein (CREB) and MYC, and thus may play a regulatory role in PKA or retinoic acid induced neuronal differentiation. Alternatively spliced transcript variants encoding different proteins have been described.[provided by RefSeq, Jul 2010]

MAP3K12 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.12897477).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001193511.2. 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
	MAP3K12	NM_001193511.2	MANE Select	c.2183C>T	p.Ser728Phe	missense	Exon 11 of 14	NP_001180440.1	Q12852-2
	MAP3K12	NM_006301.4		c.2084C>T	p.Ser695Phe	missense	Exon 12 of 15	NP_006292.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MAP3K12	ENST00000547488.6	TSL:2 MANE Select	c.2183C>T	p.Ser728Phe	missense	Exon 11 of 14	ENSP00000449038.1	Q12852-2
MAP3K12	ENST00000267079.6	TSL:1	c.2084C>T	p.Ser695Phe	missense	Exon 12 of 15	ENSP00000267079.2	Q12852-1
MAP3K12	ENST00000552365.1	TSL:1	n.*913C>T		non_coding_transcript_exon	Exon 11 of 14	ENSP00000447889.1	F8VUG4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.095

BayesDel_noAF

Benign

-0.37

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.24

Eigen

Benign

-0.42

Eigen_PC

Benign

-0.31

FATHMM_MKL

Benign

0.70

LIST_S2

Uncertain

0.91

M_CAP

Benign

0.022

MetaRNN

Benign

0.13

MetaSVM

Benign

-0.95

MutationAssessor

Benign

1.5

PhyloP100

0.61

PrimateAI

Uncertain

0.63

PROVEAN

Benign

-1.9

REVEL

Benign

0.044

Sift

Uncertain

0.0080

Sift4G

Uncertain

0.035

Polyphen

0.17

Vest4

0.32

MutPred

0.39

Gain of catalytic residue at S691 (P = 0)

MVP

0.36

MPC

0.26

ClinPred

0.61

GERP RS

3.2

Varity_R

0.17

gMVP

0.22

Mutation Taster

=89/11

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over