rs12452497

Positions:

• chr17-12140460-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_003010.4(MAP2K4):​c.1086+576A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.241 in 152,092 control chromosomes in the GnomAD database, including 4,784 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 0.24 (4784 hom., cov: 32)
• Consequence: MAP2K4 NM_003010.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.40

Genes affected

MAP2K4 (HGNC:6844): (mitogen-activated protein kinase kinase 4) This gene encodes a member of the mitogen-activated protein kinase (MAPK) family. Members of this family 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. They form a three-tiered signaling module composed of MAPKKKs, MAPKKs, and MAPKs. This protein is phosphorylated at serine and threonine residues by MAPKKKs and subsequently phosphorylates downstream MAPK targets at threonine and tyrosine residues. A similar protein in mouse has been reported to play a role in liver organogenesis. A pseudogene of this gene is located on the long arm of chromosome X. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2013]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.28 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MAP2K4	NM_003010.4	c.1086+576A>G		intron_variant		ENST00000353533.10	NP_003001.1
MAP2K4	NM_001281435.2	c.1119+576A>G		intron_variant			NP_001268364.1
MAP2K4	XM_005256753.4	c.732+576A>G		intron_variant			XP_005256810.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAP2K4	ENST00000353533.10	c.1086+576A>G		intron_variant		1	NM_003010.4	ENSP00000262445	P2

Frequencies

GnomAD3 genomes AF: 0.241 AC: 36586 AN: 151972 Hom.: 4780 Cov.: 32

Gnomad AFR AF: 0.139

Gnomad AMI AF: 0.347

Gnomad AMR AF: 0.259

Gnomad ASJ AF: 0.246

Gnomad EAS AF: 0.232

Gnomad SAS AF: 0.254

Gnomad FIN AF: 0.323

Gnomad MID AF: 0.268

Gnomad NFE AF: 0.283

Gnomad OTH AF: 0.251

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

GnomAD4 genome AF: 0.241 AC: 36606 AN: 152092 Hom.: 4784 Cov.: 32 AF XY: 0.242 AC XY: 18025 AN XY: 74352

Gnomad4 AFR AF: 0.139

Gnomad4 AMR AF: 0.259

Gnomad4 ASJ AF: 0.246

Gnomad4 EAS AF: 0.232

Gnomad4 SAS AF: 0.255

Gnomad4 FIN AF: 0.323

Gnomad4 NFE AF: 0.283

Gnomad4 OTH AF: 0.252

Alfa AF: 0.274 Hom.: 8080

Bravo AF: 0.233

Asia WGS AF: 0.218 AC: 759 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.61
DANN	Benign	0.42

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: rs12452497; hg19: chr17-12043777; COSMIC: COSV62260268;