16-30116944-C-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_002746.3(MAPK3):c.967G>A(p.Glu323Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00167 in 1,613,754 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.0014 ( 2 hom., cov: 31)

Exomes 𝑓: 0.0017 ( 4 hom. )

Consequence

MAPK3
NM_002746.3 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:2

Conservation

PhyloP100: 3.49

Variant links:

Genes affected

MAPK3 (HGNC:6877): (mitogen-activated protein kinase 3) The protein encoded by this gene is a member of the MAP kinase family. MAP kinases, also known as extracellular signal-regulated kinases (ERKs), act in a signaling cascade that regulates various cellular processes such as proliferation, differentiation, and cell cycle progression in response to a variety of extracellular signals. This kinase is activated by upstream kinases, resulting in its translocation to the nucleus where it phosphorylates nuclear targets. Alternatively spliced transcript variants encoding different protein isoforms have been described. [provided by RefSeq, Jul 2008]

MAPK3 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.012747735).

BP6

Variant 16-30116944-C-T is Benign according to our data. Variant chr16-30116944-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 718814.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High AC in GnomAd4 at 209 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAPK3	NM_002746.3 link	c.967G>A	p.Glu323Lys	missense_variant	Exon 7 of 9	ENST00000263025.9	NP_002737.2	P27361-1L7RXH5
MAPK3	NM_001040056.3 link	c.967G>A	p.Glu323Lys	missense_variant	Exon 7 of 7		NP_001035145.1	P27361-3
MAPK3	NM_001109891.2 link	c.835G>A	p.Glu279Lys	missense_variant	Exon 6 of 8		NP_001103361.1	P27361-2Q9BWJ1
MAPK3	XR_243293.2 link	n.978G>A		non_coding_transcript_exon_variant	Exon 7 of 10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAPK3	ENST00000263025.9 link	c.967G>A	p.Glu323Lys	missense_variant	Exon 7 of 9	1	NM_002746.3	ENSP00000263025.4		P27361-1

Frequencies

GnomAD3 genomes

AF:

0.00137

AC:

209

AN:

152126

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000338

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00471

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00206

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.00171

AC:

428

AN:

250840

Hom.:

AF XY:

0.00162

AC XY:

219

AN XY:

135526

show subpopulations

Gnomad AFR exome

AF:

0.000246

Gnomad AMR exome

AF:

0.0000579

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000164

Gnomad FIN exome

AF:

0.00624

Gnomad NFE exome

AF:

0.00237

Gnomad OTH exome

AF:

0.00212

GnomAD4 exome

AF:

0.00171

AC:

2494

AN:

1461510

Hom.:

Cov.:

AF XY:

0.00165

AC XY:

1199

AN XY:

727010

show subpopulations

Gnomad4 AFR exome

AF:

0.000179

Gnomad4 AMR exome

AF:

0.0000895

Gnomad4 ASJ exome

AF:

0.0000766

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000116

Gnomad4 FIN exome

AF:

0.00730

Gnomad4 NFE exome

AF:

0.00180

Gnomad4 OTH exome

AF:

0.00139

GnomAD4 genome

AF:

0.00137

AC:

209

AN:

152244

Hom.:

Cov.:

AF XY:

0.00126

AC XY:

AN XY:

74442

show subpopulations

Gnomad4 AFR

AF:

0.000337

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00471

Gnomad4 NFE

AF:

0.00206

Gnomad4 OTH

AF:

0.000474

Alfa

AF:

0.00181

Hom.:

Bravo

AF:

0.000982

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00208

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00140

AC:

ExAC

AF:

0.00201

AC:

244

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00185

EpiControl

AF:

0.00202

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

MAPK3-related disorder

Benign:1

Aug 21, 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). -

not provided

Benign:1

Dec 31, 2019

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

AlphaMissense

Benign

0.30

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.27

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.31

T;.;.;T;.;.;.

Eigen

Uncertain

0.50

Eigen_PC

Uncertain

0.51

FATHMM_MKL

Uncertain

0.86

LIST_S2

Uncertain

0.97

D;D;D;D;.;D;D

M_CAP

Benign

0.058

MetaRNN

Benign

0.013

T;T;T;T;T;T;T

MetaSVM

Benign

-0.50

MutationAssessor

Benign

1.7

L;.;.;.;.;.;L

PrimateAI

Uncertain

0.60

PROVEAN

Uncertain

-2.7

D;D;D;D;D;D;D

REVEL

Benign

0.19

Sift

Uncertain

0.011

D;D;D;D;D;D;D

Sift4G

Uncertain

0.015

D;D;D;D;D;D;D

Polyphen

0.97

D;.;P;.;P;.;P

Vest4

0.46

MVP

0.79

MPC

1.5

ClinPred

0.068

GERP RS

5.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.71

gMVP

0.63

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over