6-36107549-C-T

Variant names:

• chr6-36107549-C-T
• rs28763973
• ENST00000310795.8:c.857C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_139014.3(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 NM_139014.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -3.61
• Publications: 7 publications found

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]

ACMG classification

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: NM_139014.3. 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
	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

Sel.	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.: 47 Cov.: 33

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

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.: 34 Cov.: 31 AF XY: 0.00115 AC XY: 834 AN XY: 722896

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: 0 AN: 26070

East Asian (EAS) AF: 0.00 AC: 0 AN: 39448

South Asian (SAS) AF: 0.000393 AC: 33 AN: 83890

European-Finnish (FIN) AF: 0.000150 AC: 8 AN: 53350

Middle Eastern (MID) AF: 0.00191 AC: 11 AN: 5754

European-Non Finnish (NFE) AF: 0.0000830 AC: 92 AN: 1108316

Other (OTH) AF: 0.00246 AC: 148 AN: 60122

GnomAD4 genome AF: 0.0133 AC: 2019 AN: 152310 Hom.: 48 Cov.: 33 AF XY: 0.0131 AC XY: 974 AN XY: 74468

African (AFR) AF: 0.0454 AC: 1888 AN: 41556

American (AMR) AF: 0.00588 AC: 90 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5188

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4830

European-Finnish (FIN) AF: 0.0000943 AC: 1 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000206 AC: 14 AN: 68038

Other (OTH) AF: 0.0109 AC: 23 AN: 2116

Alfa AF: 0.00449 Hom.: 32

Bravo AF: 0.0155

ESP6500AA AF: 0.0461 AC: 203

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00437 AC: 531

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	1.7
DANN	Benign	0.67
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.044	N
LIST_S2	Benign	0.46	T
MetaRNN	Benign	0.0013	T
MetaSVM	Benign	-0.90	T
PhyloP100		-3.6
PROVEAN	Benign	1.9	N
REVEL	Benign	0.11
Sift	Benign	0.95	T
Sift4G	Uncertain	0.024	D
Polyphen		0.011	B
Vest4		0.14
MVP		0.37
ClinPred		0.015	T
GERP RS		-12
Mutation Taster		=98/2	polymorphism

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

Other links and lift over

dbSNP: rs28763973; hg19: chr6-36075326;