16-30123098-C-A

Variant summary

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

The NM_002746.3(MAPK3):c.112G>T(p.Val38Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000702 in 1,423,814 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 28)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: MAPK3 NM_002746.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.50

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

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=0.27596158).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MAPK3	NM_002746.3	c.112G>T	p.Val38Leu	missense_variant	1/9	ENST00000263025.9
MAPK3	NM_001040056.3	c.112G>T	p.Val38Leu	missense_variant	1/7
MAPK3	NM_001109891.2	c.112G>T	p.Val38Leu	missense_variant	1/8
MAPK3	XR_243293.2	n.123G>T		non_coding_transcript_exon_variant	1/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAPK3	ENST00000263025.9	c.112G>T	p.Val38Leu	missense_variant	1/9	1	NM_002746.3	P1

Frequencies

GnomAD3 genomes Cov.: 28

GnomAD4 exome AF: 7.02e-7 AC: 1 AN: 1423814 Hom.: 0 Cov.: 36 AF XY: 0.00 AC XY: 0 AN XY: 708456

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.14e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 28

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 28, 2022

The c.112G>T (p.V38L) alteration is located in exon 1 (coding exon 1) of the MAPK3 gene. This alteration results from a G to T substitution at nucleotide position 112, causing the valine (V) at amino acid position 38 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
Cadd	Uncertain	24
Dann	Uncertain	0.99
DEOGEN2	Benign	0.27	T;.;T;.;.
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.056
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.93	D;D;D;.;D
M_CAP	Pathogenic	0.66	D
MetaRNN	Benign	0.28	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N;N;.;N;N
MutationTaster	Benign	0.99	D;D;D;D;D;D
PrimateAI	Pathogenic	0.96	D
PROVEAN	Benign	-1.6	N;N;N;N;N
REVEL	Benign	0.069
Sift	Benign	0.064	T;T;T;T;T
Sift4G	Benign	0.067	T;T;T;T;T
Polyphen		0.0040	B;B;.;B;B
Vest4		0.19
MutPred		0.56		Gain of catalytic residue at V38 (P = 0.1576);Gain of catalytic residue at V38 (P = 0.1576);.;Gain of catalytic residue at V38 (P = 0.1576);Gain of catalytic residue at V38 (P = 0.1576);
MVP		0.67
MPC		0.65
ClinPred		0.50	D
GERP RS		3.7
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.2
Varity_R		0.79
gMVP		0.51

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: rs1394035337; hg19: chr16-30134419;