Genetic Variant ENST00000310795.8:c.857C>T (chr6-36107549-C-T) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The ENST00000310795.8(MAPK14):c.857C>T(p.Thr286Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0025 in 1,606,390 control chromosomes in the GnomAD database, including 82 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.013 ( 48 hom., cov: 33)

Exomes 𝑓: 0.0014 ( 34 hom. )

Consequence

MAPK14
ENST00000310795.8 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -3.61

Publications

7 publications found

Variant links:

Genes affected

MAPK14 (HGNC:6876): (mitogen-activated protein kinase 14) The protein encoded by this gene is a member of the MAP kinase family. MAP kinases act as an integration point for multiple biochemical signals, and are involved in a wide variety of cellular processes such as proliferation, differentiation, transcription regulation and development. This kinase is activated by various environmental stresses and proinflammatory cytokines. The activation requires its phosphorylation by MAP kinase kinases (MKKs), or its autophosphorylation triggered by the interaction of MAP3K7IP1/TAB1 protein with this kinase. The substrates of this kinase include transcription regulator ATF2, MEF2C, and MAX, cell cycle regulator CDC25B, and tumor suppressor p53, which suggest the roles of this kinase in stress related transcription and cell cycle regulation, as well as in genotoxic stress response. Four alternatively spliced transcript variants of this gene encoding distinct isoforms have been reported. [provided by RefSeq, Jul 2008]

MAPK14 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0012913942).

BP6

Variant 6-36107549-C-T is Benign according to our data. Variant chr6-36107549-C-T is described in ClinVar as Benign. ClinVar VariationId is 782474.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0133 (2019/152310) while in subpopulation AFR AF = 0.0454 (1888/41556). AF 95% confidence interval is 0.0437. There are 48 homozygotes in GnomAd4. There are 974 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 2019 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000310795.8. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MAPK14	NM_139012.3	MANE Select	c.936C>T	p.His312His	synonymous	Exon 11 of 12	NP_620581.1	Q16539-1
MAPK14	NM_139014.3		c.857C>T	p.Thr286Met	missense	Exon 10 of 11	NP_620583.1	Q16539-4
MAPK14	NM_001315.3		c.936C>T	p.His312His	synonymous	Exon 11 of 12	NP_001306.1	L7RSM2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MAPK14	ENST00000310795.8	TSL:1	c.857C>T	p.Thr286Met	missense	Exon 10 of 11	ENSP00000308669.4	Q16539-4
MAPK14	ENST00000229794.9	TSL:1 MANE Select	c.936C>T	p.His312His	synonymous	Exon 11 of 12	ENSP00000229794.4	Q16539-1
MAPK14	ENST00000229795.8	TSL:1	c.936C>T	p.His312His	synonymous	Exon 11 of 12	ENSP00000229795.3	Q16539-2

Frequencies

GnomAD3 genomes

AF:

0.0132

AC:

2012

AN:

152192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0454

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00589

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.0000943

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000206

Gnomad OTH

AF:

0.0110

GnomAD2 exomes

AF:

0.00337

AC:

830

AN:

246292

AF XY:

0.00237

show subpopulations

Gnomad AFR exome

AF:

0.0427

Gnomad AMR exome

AF:

0.00315

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000553

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.000142

Gnomad OTH exome

AF:

0.00152

GnomAD4 exome

AF:

0.00137

AC:

1994

AN:

1454080

Hom.:

Cov.:

AF XY:

0.00115

AC XY:

834

AN XY:

722896

show subpopulations

African (AFR)

AF:

0.0466

AC:

1551

AN:

33290

American (AMR)

AF:

0.00344

AC:

151

AN:

43840

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26070

East Asian (EAS)

AF:

0.00

AC:

AN:

39448

South Asian (SAS)

AF:

0.000393

AC:

AN:

83890

European-Finnish (FIN)

AF:

0.000150

AC:

AN:

53350

Middle Eastern (MID)

AF:

0.00191

AC:

AN:

5754

European-Non Finnish (NFE)

AF:

0.0000830

AC:

AN:

1108316

Other (OTH)

AF:

0.00246

AC:

148

AN:

60122

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

187

281

374

468

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

104

156

208

260

<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:

0.0133

AC:

2019

AN:

152310

Hom.:

Cov.:

AF XY:

0.0131

AC XY:

974

AN XY:

74468

show subpopulations

African (AFR)

AF:

0.0454

AC:

1888

AN:

41556

American (AMR)

AF:

0.00588

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5188

South Asian (SAS)

AF:

0.000414

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.0000943

AC:

AN:

10604

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000206

AC:

AN:

68038

Other (OTH)

AF:

0.0109

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

104

208

312

416

520

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

110

<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:

0.00449

Hom.:

Bravo

AF:

0.0155

ESP6500AA

AF:

0.0461

AC:

203

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00437

AC:

531

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.55

CADD

Benign

1.7

(source)

DANN

Benign

0.67

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.044

LIST_S2

Benign

0.46

MetaRNN

Benign

0.0013

MetaSVM

Benign

-0.90

PhyloP100

-3.6

PROVEAN

Benign

1.9

REVEL

Benign

0.11

Sift

Benign

0.95

Sift4G

Uncertain

0.024

Polyphen

0.011

Vest4

0.14

MVP

0.37

ClinPred

0.015

GERP RS

-12

Mutation Taster

=98/2

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over