3-50611939-C-G

Variant names:

• chr3-50611939-C-G
• rs6768300
• ENST00000446044.5:c.-565C>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000446044.5(MAPKAPK3):​c.-565C>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.876 in 427,370 control chromosomes in the GnomAD database, including 164,583 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.85 (55408 hom., cov: 38)
  • Exomes 𝑓: 0.89 (109175 hom.)
• Consequence: MAPKAPK3 ENST00000446044.5 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.332
• Publications: 10 publications found

Genes affected

MAPKAPK3 (HGNC:6888): (MAPK activated protein kinase 3) This gene encodes a member of the Ser/Thr protein kinase family. This kinase functions as a mitogen-activated protein kinase (MAP kinase)- activated protein kinase. MAP kinases are also known as extracellular signal-regulated kinases (ERKs), act as an integration point for multiple biochemical signals. This kinase was shown to be activated by growth inducers and stress stimulation of cells. In vitro studies demonstrated that ERK, p38 MAP kinase and Jun N-terminal kinase were all able to phosphorylate and activate this kinase, which suggested the role of this kinase as an integrative element of signaling in both mitogen and stress responses. This kinase was reported to interact with, phosphorylate and repress the activity of E47, which is a basic helix-loop-helix transcription factor known to be involved in the regulation of tissue-specific gene expression and cell differentiation. Alternate splicing results in multiple transcript variants that encode the same protein. [provided by RefSeq, Sep 2011]

CISH (HGNC:1984): (cytokine inducible SH2 containing protein) The protein encoded by this gene contains a SH2 domain and a SOCS box domain. The protein thus belongs to the cytokine-induced STAT inhibitor (CIS), also known as suppressor of cytokine signaling (SOCS) or STAT-induced STAT inhibitor (SSI), protein family. CIS family members are known to be cytokine-inducible negative regulators of cytokine signaling. The expression of this gene can be induced by IL2, IL3, GM-CSF and EPO in hematopoietic cells. Proteasome-mediated degradation of this protein has been shown to be involved in the inactivation of the erythropoietin receptor. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2008]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.923 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CISH	NM_145071.4	c.-289G>C		upstream_gene_variant		ENST00000348721.4	NP_659508.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CISH	ENST00000348721.4	c.-289G>C		upstream_gene_variant		1	NM_145071.4	ENSP00000294173.3

Frequencies

GnomAD3 genomes AF: 0.851 AC: 129426 AN: 152140 Hom.: 55398 Cov.: 38

Gnomad AFR AF: 0.760

Gnomad AMI AF: 0.878

Gnomad AMR AF: 0.872

Gnomad ASJ AF: 0.940

Gnomad EAS AF: 0.945

Gnomad SAS AF: 0.917

Gnomad FIN AF: 0.882

Gnomad MID AF: 0.914

Gnomad NFE AF: 0.879

Gnomad OTH AF: 0.874

GnomAD4 exome AF: 0.890 AC: 244880 AN: 275114 Hom.: 109175 Cov.: 4 AF XY: 0.891 AC XY: 126161 AN XY: 141630

African (AFR) AF: 0.761 AC: 5326 AN: 7000

American (AMR) AF: 0.881 AC: 6264 AN: 7110

Ashkenazi Jewish (ASJ) AF: 0.942 AC: 9117 AN: 9682

East Asian (EAS) AF: 0.944 AC: 21090 AN: 22344

South Asian (SAS) AF: 0.932 AC: 10600 AN: 11372

European-Finnish (FIN) AF: 0.876 AC: 20106 AN: 22944

Middle Eastern (MID) AF: 0.938 AC: 1317 AN: 1404

European-Non Finnish (NFE) AF: 0.885 AC: 155560 AN: 175764

Other (OTH) AF: 0.886 AC: 15500 AN: 17494

GnomAD4 genome AF: 0.850 AC: 129480 AN: 152256 Hom.: 55408 Cov.: 38 AF XY: 0.852 AC XY: 63468 AN XY: 74456

African (AFR) AF: 0.759 AC: 31518 AN: 41530

American (AMR) AF: 0.872 AC: 13350 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.940 AC: 3263 AN: 3472

East Asian (EAS) AF: 0.945 AC: 4873 AN: 5154

South Asian (SAS) AF: 0.916 AC: 4424 AN: 4830

European-Finnish (FIN) AF: 0.882 AC: 9367 AN: 10624

Middle Eastern (MID) AF: 0.914 AC: 267 AN: 292

European-Non Finnish (NFE) AF: 0.879 AC: 59778 AN: 68024

Other (OTH) AF: 0.872 AC: 1839 AN: 2110

Alfa AF: 0.851 Hom.: 6900

Bravo AF: 0.846

Asia WGS AF: 0.892 AC: 3097 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	9.1
DANN	Benign	0.67
PhyloP100		0.33
PromoterAI		-0.11	Neutral
Mutation Taster		=300/0	polymorphism (auto)

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: rs6768300; hg19: chr3-50649370;