rs1570056

Variant names:

• chr6-136738789-T-C
• rs1570056
• NM_005923.4:c.449-18200A>G

Variant summary

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

The ENST00000359015.5(MAP3K5):​c.449-18200A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.514 in 151,724 control chromosomes in the GnomAD database, including 20,505 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 0.51 (20505 hom., cov: 32)
• Consequence: MAP3K5 ENST00000359015.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.01
• Publications: 7 publications found

Genes affected

MAP3K5 (HGNC:6857): (mitogen-activated protein kinase kinase kinase 5) Mitogen-activated protein kinase (MAPK) signaling cascades include MAPK or extracellular signal-regulated kinase (ERK), MAPK kinase (MKK or MEK), and MAPK kinase kinase (MAPKKK or MEKK). MAPKK kinase/MEKK phosphorylates and activates its downstream protein kinase, MAPK kinase/MEK, which in turn activates MAPK. The kinases of these signaling cascades are highly conserved, and homologs exist in yeast, Drosophila, and mammalian cells. MAPKKK5 contains 1,374 amino acids with all 11 kinase subdomains. Northern blot analysis shows that MAPKKK5 transcript is abundantly expressed in human heart and pancreas. The MAPKKK5 protein phosphorylates and activates MKK4 (aliases SERK1, MAPKK4) in vitro, and activates c-Jun N-terminal kinase (JNK)/stress-activated protein kinase (SAPK) during transient expression in COS and 293 cells; MAPKKK5 does not activate MAPK/ERK. [provided by RefSeq, Jul 2008]

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.627 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000359015.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAP3K5	NM_005923.4	MANE Select	c.449-18200A>G		intron	N/A	NP_005914.1
	MAP3K5	NM_001438058.1		c.776-18200A>G		intron	N/A	NP_001424987.1
	MAP3K5	NM_001438579.1		c.7-33656A>G		intron	N/A	NP_001425508.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAP3K5	ENST00000359015.5	TSL:1 MANE Select	c.449-18200A>G		intron	N/A	ENSP00000351908.4
	MAP3K5	ENST00000698928.1		c.776-18200A>G		intron	N/A	ENSP00000514039.1

Frequencies

GnomAD3 genomes AF: 0.513 AC: 77835 AN: 151604 Hom.: 20445 Cov.: 32

Gnomad AFR AF: 0.632

Gnomad AMI AF: 0.594

Gnomad AMR AF: 0.414

Gnomad ASJ AF: 0.447

Gnomad EAS AF: 0.474

Gnomad SAS AF: 0.439

Gnomad FIN AF: 0.472

Gnomad MID AF: 0.516

Gnomad NFE AF: 0.481

Gnomad OTH AF: 0.500

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

GnomAD4 genome AF: 0.514 AC: 77953 AN: 151724 Hom.: 20505 Cov.: 32 AF XY: 0.509 AC XY: 37713 AN XY: 74116

African (AFR) AF: 0.633 AC: 26227 AN: 41424

American (AMR) AF: 0.413 AC: 6311 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.447 AC: 1548 AN: 3464

East Asian (EAS) AF: 0.474 AC: 2433 AN: 5138

South Asian (SAS) AF: 0.438 AC: 2107 AN: 4806

European-Finnish (FIN) AF: 0.472 AC: 4943 AN: 10468

Middle Eastern (MID) AF: 0.531 AC: 156 AN: 294

European-Non Finnish (NFE) AF: 0.481 AC: 32630 AN: 67854

Other (OTH) AF: 0.504 AC: 1061 AN: 2104

Alfa AF: 0.487 Hom.: 3161

Bravo AF: 0.517

Asia WGS AF: 0.470 AC: 1636 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.63
DANN	Benign	0.36
PhyloP100		-1.0
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: rs1570056; hg19: chr6-137059927;