16-30116903-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_002746.3(MAPK3):c.1008G>A(p.Pro336=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00274 in 1,613,914 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0027 (2 hom., cov: 31)
  • Exomes 𝑓: 0.0027 (12 hom.)
• Consequence: MAPK3 NM_002746.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.480

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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 16-30116903-C-T is Benign according to our data. Variant chr16-30116903-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 710826.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.48 with no splicing effect.
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00274 (3998/1461706) while in subpopulation MID AF= 0.0218 (126/5768). AF 95% confidence interval is 0.0187. There are 12 homozygotes in gnomad4_exome. There are 1993 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 420 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MAPK3	NM_002746.3	c.1008G>A	p.Pro336=	synonymous_variant	7/9	ENST00000263025.9
MAPK3	NM_001040056.3	c.1008G>A	p.Pro336=	synonymous_variant	7/7
MAPK3	NM_001109891.2	c.876G>A	p.Pro292=	synonymous_variant	6/8
MAPK3	XR_243293.2	n.1019G>A		non_coding_transcript_exon_variant	7/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAPK3	ENST00000263025.9	c.1008G>A	p.Pro336=	synonymous_variant	7/9	1	NM_002746.3	P1

Frequencies

GnomAD3 genomes AF: 0.00276 AC: 420 AN: 152090 Hom.: 2 Cov.: 31

Gnomad AFR AF: 0.00138

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00694

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00188

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.00301

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00311 AC: 780 AN: 250820 Hom.: 3 AF XY: 0.00318 AC XY: 431 AN XY: 135602

Gnomad AFR exome AF: 0.00123

Gnomad AMR exome AF: 0.00420

Gnomad ASJ exome AF: 0.00528

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000948

Gnomad FIN exome AF: 0.00217

Gnomad NFE exome AF: 0.00395

Gnomad OTH exome AF: 0.00638

GnomAD4 exome AF: 0.00274 AC: 3998 AN: 1461706 Hom.: 12 Cov.: 32 AF XY: 0.00274 AC XY: 1993 AN XY: 727140

Gnomad4 AFR exome AF: 0.00137

Gnomad4 AMR exome AF: 0.00398

Gnomad4 ASJ exome AF: 0.00528

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00123

Gnomad4 FIN exome AF: 0.00300

Gnomad4 NFE exome AF: 0.00274

Gnomad4 OTH exome AF: 0.00325

GnomAD4 genome AF: 0.00275 AC: 418 AN: 152208 Hom.: 2 Cov.: 31 AF XY: 0.00280 AC XY: 208 AN XY: 74400

Gnomad4 AFR AF: 0.00135

Gnomad4 AMR AF: 0.00693

Gnomad4 ASJ AF: 0.00317

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.00188

Gnomad4 NFE AF: 0.00301

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00310 Hom.: 0

Bravo AF: 0.00295

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00420

EpiControl AF: 0.00367

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2023	MAPK3: BP4, BP7, BS2 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 31, 2019	- -

MAPK3-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 28, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
Cadd	Benign	6.7
Dann	Benign	0.63
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs1143695; hg19: chr16-30128224;