rs55859133

Variant names:

• chr16-30116944-C-T
• rs55859133
• NM_002746.3:c.967G>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_002746.3(MAPK3):​c.967G>A​(p.Glu323Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00167 in 1,613,754 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0014 (2 hom., cov: 31)
  • Exomes 𝑓: 0.0017 (4 hom.)
• Consequence: MAPK3 NM_002746.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 3.49
• Publications: 12 publications found

Genes affected

MAPK3 (HGNC:6877): (mitogen-activated protein kinase 3) The protein encoded by this gene is a member of the MAP kinase family. MAP kinases, also known as extracellular signal-regulated kinases (ERKs), act in a signaling cascade that regulates various cellular processes such as proliferation, differentiation, and cell cycle progression in response to a variety of extracellular signals. This kinase is activated by upstream kinases, resulting in its translocation to the nucleus where it phosphorylates nuclear targets. Alternatively spliced transcript variants encoding different protein isoforms have been described. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.012747735).
• BP6: Variant 16-30116944-C-T is Benign according to our data. Variant chr16-30116944-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 718814.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 209 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002746.3. 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
	MAPK3	NM_002746.3	MANE Select	c.967G>A	p.Glu323Lys	missense	Exon 7 of 9	NP_002737.2	L7RXH5
	MAPK3	NM_001040056.3		c.967G>A	p.Glu323Lys	missense	Exon 7 of 7	NP_001035145.1	P27361-3
	MAPK3	NM_001109891.2		c.835G>A	p.Glu279Lys	missense	Exon 6 of 8	NP_001103361.1	P27361-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAPK3	ENST00000263025.9	TSL:1 MANE Select	c.967G>A	p.Glu323Lys	missense	Exon 7 of 9	ENSP00000263025.4	P27361-1
	MAPK3	ENST00000395199.7	TSL:1	c.967G>A	p.Glu323Lys	missense	Exon 7 of 7	ENSP00000378625.3	P27361-3
	MAPK3	ENST00000395202.5	TSL:1	c.835G>A	p.Glu279Lys	missense	Exon 6 of 7	ENSP00000378628.1	P27361-2

Frequencies

GnomAD3 genomes AF: 0.00137 AC: 209 AN: 152126 Hom.: 2 Cov.: 31

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00471

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00206

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.00171 AC: 428 AN: 250840 AF XY: 0.00162

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00624

Gnomad NFE exome AF: 0.00237

Gnomad OTH exome AF: 0.00212

GnomAD4 exome AF: 0.00171 AC: 2494 AN: 1461510 Hom.: 4 Cov.: 32 AF XY: 0.00165 AC XY: 1199 AN XY: 727010

African (AFR) AF: 0.000179 AC: 6 AN: 33478

American (AMR) AF: 0.0000895 AC: 4 AN: 44686

Ashkenazi Jewish (ASJ) AF: 0.0000766 AC: 2 AN: 26098

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.000116 AC: 10 AN: 86198

European-Finnish (FIN) AF: 0.00730 AC: 390 AN: 53402

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00180 AC: 1996 AN: 1111810

Other (OTH) AF: 0.00139 AC: 84 AN: 60372

GnomAD4 genome AF: 0.00137 AC: 209 AN: 152244 Hom.: 2 Cov.: 31 AF XY: 0.00126 AC XY: 94 AN XY: 74442

African (AFR) AF: 0.000337 AC: 14 AN: 41536

American (AMR) AF: 0.000196 AC: 3 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.00471 AC: 50 AN: 10618

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

European-Non Finnish (NFE) AF: 0.00206 AC: 140 AN: 68018

Other (OTH) AF: 0.000474 AC: 1 AN: 2110

Alfa AF: 0.00185 Hom.: 0

Bravo AF: 0.000982

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00208 AC: 8

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00140 AC: 12

ExAC AF: 0.00201 AC: 244

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00185

EpiControl AF: 0.00202

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	MAPK3-related disorder (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.27
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.31	T
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.058	D
MetaRNN	Benign	0.013	T
MetaSVM	Benign	-0.50	T
MutationAssessor	Benign	1.7	L
PhyloP100		3.5
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-2.7	D
REVEL	Benign	0.19
Sift	Uncertain	0.011	D
Sift4G	Uncertain	0.015	D
Polyphen		0.97	D
Vest4		0.46
MVP		0.79
MPC		1.5
ClinPred		0.068	T
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.71
gMVP		0.63
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: rs55859133; hg19: chr16-30128265;