rs9610417

Variant names:

• chr22-21845681-C-T
• rs9610417
• NM_002745.5:c.119+21641G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002745.5(MAPK1):​c.119+21641G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.178 in 152,188 control chromosomes in the GnomAD database, including 2,786 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.18 (2786 hom., cov: 32)
• Consequence: MAPK1 NM_002745.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0700
• Publications: 27 publications found

Genes affected

MAPK1 (HGNC:6871): (mitogen-activated protein kinase 1) This gene encodes a member of the MAP kinase family. MAP kinases, also known as extracellular signal-regulated kinases (ERKs), act as an integration point for multiple biochemical signals, and are involved in a wide variety of cellular processes such as proliferation, differentiation, transcription regulation and development. The activation of this kinase requires its phosphorylation by upstream kinases. Upon activation, this kinase translocates to the nucleus of the stimulated cells, where it phosphorylates nuclear targets. One study also suggests that this protein acts as a transcriptional repressor independent of its kinase activity. The encoded protein has been identified as a moonlighting protein based on its ability to perform mechanistically distinct functions. Two alternatively spliced transcript variants encoding the same protein, but differing in the UTRs, have been reported for this gene. [provided by RefSeq, Jan 2014]

MAPK1 Gene-Disease associations (from GenCC):

• Noonan syndrome 13

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.231 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAPK1	NM_002745.5	c.119+21641G>A		intron_variant	Intron 1 of 8	ENST00000215832.11	NP_002736.3
MAPK1	NM_138957.3	c.119+21641G>A		intron_variant	Intron 1 of 7		NP_620407.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAPK1	ENST00000215832.11	c.119+21641G>A		intron_variant	Intron 1 of 8	1	NM_002745.5	ENSP00000215832.7
MAPK1	ENST00000398822.7	c.119+21641G>A		intron_variant	Intron 1 of 7	1		ENSP00000381803.3
MAPK1	ENST00000544786.1	c.119+21641G>A		intron_variant	Intron 1 of 6	1		ENSP00000440842.1

Frequencies

GnomAD3 genomes AF: 0.178 AC: 27043 AN: 152070 Hom.: 2782 Cov.: 32

Gnomad AFR AF: 0.0910

Gnomad AMI AF: 0.229

Gnomad AMR AF: 0.189

Gnomad ASJ AF: 0.262

Gnomad EAS AF: 0.0987

Gnomad SAS AF: 0.101

Gnomad FIN AF: 0.178

Gnomad MID AF: 0.231

Gnomad NFE AF: 0.234

Gnomad OTH AF: 0.207

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.178 AC: 27048 AN: 152188 Hom.: 2786 Cov.: 32 AF XY: 0.175 AC XY: 13008 AN XY: 74414

African (AFR) AF: 0.0909 AC: 3776 AN: 41530

American (AMR) AF: 0.189 AC: 2885 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.262 AC: 909 AN: 3466

East Asian (EAS) AF: 0.0989 AC: 512 AN: 5176

South Asian (SAS) AF: 0.101 AC: 489 AN: 4828

European-Finnish (FIN) AF: 0.178 AC: 1882 AN: 10586

Middle Eastern (MID) AF: 0.231 AC: 68 AN: 294

European-Non Finnish (NFE) AF: 0.234 AC: 15887 AN: 67994

Other (OTH) AF: 0.204 AC: 432 AN: 2114

Alfa AF: 0.209 Hom.: 8394

Bravo AF: 0.173

Asia WGS AF: 0.105 AC: 366 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	5.1
DANN	Benign	0.65
PhyloP100		-0.070
Mutation Taster		=100/0	polymorphism (auto)

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: rs9610417; hg19: chr22-22199970;