rs4363056

Variant names:

• chr6-136676481-C-T
• rs4363056
• NM_005923.4:c.1254-7086G>A

Variant summary

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

The NM_005923.4(MAP3K5):​c.1254-7086G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.714 in 152,072 control chromosomes in the GnomAD database, including 40,072 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 0.71 (40072 hom., cov: 32)
• Consequence: MAP3K5 NM_005923.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -5.02
• Publications: 9 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=-1.03).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.908 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAP3K5	NM_005923.4	c.1254-7086G>A		intron_variant	Intron 7 of 29	ENST00000359015.5	NP_005914.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAP3K5	ENST00000359015.5	c.1254-7086G>A		intron_variant	Intron 7 of 29	1	NM_005923.4	ENSP00000351908.4
MAP3K5	ENST00000698928.1	c.1581-7086G>A		intron_variant	Intron 8 of 30			ENSP00000514039.1

Frequencies

GnomAD3 genomes AF: 0.714 AC: 108420 AN: 151954 Hom.: 40024 Cov.: 32

Gnomad AFR AF: 0.916

Gnomad AMI AF: 0.630

Gnomad AMR AF: 0.677

Gnomad ASJ AF: 0.626

Gnomad EAS AF: 0.658

Gnomad SAS AF: 0.695

Gnomad FIN AF: 0.626

Gnomad MID AF: 0.671

Gnomad NFE AF: 0.623

Gnomad OTH AF: 0.707

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

GnomAD4 genome AF: 0.714 AC: 108527 AN: 152072 Hom.: 40072 Cov.: 32 AF XY: 0.711 AC XY: 52872 AN XY: 74324

African (AFR) AF: 0.916 AC: 38057 AN: 41548

American (AMR) AF: 0.677 AC: 10338 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.626 AC: 2172 AN: 3470

East Asian (EAS) AF: 0.658 AC: 3396 AN: 5164

South Asian (SAS) AF: 0.693 AC: 3340 AN: 4818

European-Finnish (FIN) AF: 0.626 AC: 6606 AN: 10548

Middle Eastern (MID) AF: 0.670 AC: 197 AN: 294

European-Non Finnish (NFE) AF: 0.623 AC: 42349 AN: 67940

Other (OTH) AF: 0.709 AC: 1499 AN: 2114

Alfa AF: 0.643 Hom.: 50335

Bravo AF: 0.725

Asia WGS AF: 0.704 AC: 2445 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.014
DANN	Benign	0.58
PhyloP100		-5.0
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: rs4363056; hg19: chr6-136997619;