6-36107549-C-T

Position:

• chr6-36107549-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

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. 11/14 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
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -3.61

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

Verdict is Benign. Variant got -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 id 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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 2019 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MAPK14	NM_139012.3	c.936C>T	p.His312=	synonymous_variant	11/12	ENST00000229794.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAPK14	ENST00000229794.9	c.936C>T	p.His312=	synonymous_variant	11/12	1	NM_139012.3	P3

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

GnomAD3 exomes AF: 0.00337 AC: 830 AN: 246292 Hom.: 16 AF XY: 0.00237 AC XY: 316 AN XY: 133060

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 SAS exome AF: 0.000512

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

Gnomad4 AFR exome AF: 0.0466

Gnomad4 AMR exome AF: 0.00344

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000393

Gnomad4 FIN exome AF: 0.000150

Gnomad4 NFE exome AF: 0.0000830

Gnomad4 OTH exome AF: 0.00246

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

Gnomad4 AFR AF: 0.0454

Gnomad4 AMR AF: 0.00588

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.0000943

Gnomad4 NFE AF: 0.000206

Gnomad4 OTH AF: 0.0109

Alfa AF: 0.00247 Hom.: 12

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

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 19, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
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
MutationTaster	Benign	1.0	D;D;D;N
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

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

Other links and lift over

dbSNP: rs28763973; hg19: chr6-36075326;