17-21300629-G-T

Variant names:

• chr17-21300629-G-T
• rs2305873
• NM_145109.3:c.250G>T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_145109.3(MAP2K3):​c.250G>T​(p.Ala84Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000287 in 1,392,696 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A84T) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 72)
  • Exomes 𝑓: 0.0000029 (0 hom.)
• Consequence: MAP2K3 NM_145109.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.21

Genes affected

MAP2K3 (HGNC:6843): (mitogen-activated protein kinase kinase 3) The protein encoded by this gene is a dual specificity protein kinase that belongs to the MAP kinase kinase family. This kinase is activated by mitogenic and environmental stress, and participates in the MAP kinase-mediated signaling cascade. It phosphorylates and thus activates MAPK14/p38-MAPK. This kinase can be activated by insulin, and is necessary for the expression of glucose transporter. Expression of RAS oncogene is found to result in the accumulation of the active form of this kinase, which thus leads to the constitutive activation of MAPK14, and confers oncogenic transformation of primary cells. The inhibition of this kinase is involved in the pathogenesis of Yersina pseudotuberculosis. Multiple alternatively spliced transcript variants that encode distinct isoforms have been reported for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.26578927).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAP2K3	NM_145109.3	c.250G>T	p.Ala84Ser	missense_variant	Exon 4 of 12	ENST00000342679.9	NP_659731.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAP2K3	ENST00000342679.9	c.250G>T	p.Ala84Ser	missense_variant	Exon 4 of 12	1	NM_145109.3	ENSP00000345083.4

Frequencies

GnomAD3 genomes Cov.: 72

GnomAD3 exomes AF: 0.00000597 AC: 1 AN: 167508 Hom.: 0 AF XY: 0.0000110 AC XY: 1 AN XY: 90704

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000132

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000287 AC: 4 AN: 1392696 Hom.: 0 Cov.: 86 AF XY: 0.00000288 AC XY: 2 AN XY: 693364

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000516

Gnomad4 SAS exome AF: 0.0000122

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.46e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 72

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Uncertain	0.031	T
BayesDel_noAF	Benign	-0.19
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Benign	0.065	T;T;.;.;.
Eigen	Benign	0.17
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.94	D;D;D;.;.
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.27	T;T;T;T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.66	N;.;.;.;.
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.16	N;N;N;.;.
REVEL	Benign	0.093
Sift	Benign	0.31	T;T;T;.;.
Sift4G	Benign	0.46	T;T;T;T;T
Polyphen		0.75	P;.;.;.;.
Vest4		0.50
MutPred		0.38		Gain of disorder (P = 0.0319);.;.;.;.;
MVP		0.67
MPC		0.14
ClinPred		0.36	T
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.062
gMVP		0.26

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs2305873; hg19: chr17-21203941;