3-50617648-CGG-CGGG

Variant names:

• chr3-50617648-C-CG
• rs751967432
• NM_001243925.2:c.90dupG

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_001243925.2(MAPKAPK3):​c.90dupG​(p.Arg31AlafsTer47) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000077 in 1,609,416 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000081 (0 hom.)
• Consequence: MAPKAPK3 NM_001243925.2 frameshift
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.386
• Publications: 4 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]

MAPKAPK3 Gene-Disease associations (from GenCC):

• patterned macular dystrophy 3

  Inheritance: AD, Unknown Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BS2: High AC in GnomAd4 at 6 AD,Unknown gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001243925.2. 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
	MAPKAPK3	NM_001243925.2	MANE Select	c.90dupG	p.Arg31AlafsTer47	frameshift	Exon 2 of 11	NP_001230854.1	Q16644
	MAPKAPK3	NM_001243926.2		c.90dupG	p.Arg31AlafsTer47	frameshift	Exon 4 of 13	NP_001230855.1	Q16644
	MAPKAPK3	NM_004635.5		c.90dupG	p.Arg31AlafsTer47	frameshift	Exon 2 of 11	NP_004626.1	Q16644

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAPKAPK3	ENST00000621469.5	TSL:1 MANE Select	c.90dupG	p.Arg31AlafsTer47	frameshift	Exon 2 of 11	ENSP00000478922.1	Q16644
	MAPKAPK3	ENST00000357955.6	TSL:1	c.90dupG	p.Arg31AlafsTer47	frameshift	Exon 2 of 11	ENSP00000350639.2	Q16644
	MAPKAPK3	ENST00000446044.5	TSL:1	c.90dupG	p.Arg31AlafsTer47	frameshift	Exon 4 of 13	ENSP00000396467.1	Q16644

Frequencies

GnomAD3 genomes AF: 0.0000395 AC: 6 AN: 152030 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000820 AC: 20 AN: 243800 AF XY: 0.0000602

Gnomad AFR exome AF: 0.000130

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000204

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000130

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000810 AC: 118 AN: 1457268 Hom.: 0 Cov.: 30 AF XY: 0.0000828 AC XY: 60 AN XY: 725002

African (AFR) AF: 0.0000299 AC: 1 AN: 33410

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26112

East Asian (EAS) AF: 0.00 AC: 0 AN: 39682

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86180

European-Finnish (FIN) AF: 0.000514 AC: 27 AN: 52538

Middle Eastern (MID) AF: 0.000181 AC: 1 AN: 5532

European-Non Finnish (NFE) AF: 0.0000749 AC: 83 AN: 1108872

Other (OTH) AF: 0.0000498 AC: 3 AN: 60220

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152148 Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3 AN XY: 74364

African (AFR) AF: 0.0000481 AC: 2 AN: 41542

American (AMR) AF: 0.00 AC: 0 AN: 15276

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5154

South Asian (SAS) AF: 0.00 AC: 0 AN: 4808

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

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

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 67982

Other (OTH) AF: 0.00 AC: 0 AN: 2104

Alfa AF: 0.000130 Hom.: 0

EpiCase AF: 0.0000546

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.39
Mutation Taster		=15/185	disease causing (fs/PTC)

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: rs751967432; hg19: chr3-50655079; COSMIC: COSV63597517; COSMIC: COSV63597517;