NM_005923.4:c.448+11122A>G

Variant names:

• chr6-136780588-T-C
• rs1570054
• NM_005923.4:c.448+11122A>G

Variant summary

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

The NM_005923.4(MAP3K5):​c.448+11122A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.624 in 152,010 control chromosomes in the GnomAD database, including 29,696 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 0.62 (29696 hom., cov: 32)
• Consequence: MAP3K5 NM_005923.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.278
• Publications: 11 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=-0.93).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.661 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005923.4. 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.448+11122A>G		intron	N/A	NP_005914.1
	MAP3K5	NM_001438058.1		c.775+11122A>G		intron	N/A	NP_001424987.1
	MAP3K5	NM_001438579.1		c.6+11122A>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.448+11122A>G		intron	N/A	ENSP00000351908.4
	MAP3K5	ENST00000698928.1		c.775+11122A>G		intron	N/A	ENSP00000514039.1

Frequencies

GnomAD3 genomes AF: 0.624 AC: 94798 AN: 151894 Hom.: 29679 Cov.: 32

Gnomad AFR AF: 0.633

Gnomad AMI AF: 0.476

Gnomad AMR AF: 0.671

Gnomad ASJ AF: 0.660

Gnomad EAS AF: 0.566

Gnomad SAS AF: 0.617

Gnomad FIN AF: 0.560

Gnomad MID AF: 0.551

Gnomad NFE AF: 0.624

Gnomad OTH AF: 0.610

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

GnomAD4 genome AF: 0.624 AC: 94856 AN: 152010 Hom.: 29696 Cov.: 32 AF XY: 0.622 AC XY: 46192 AN XY: 74270

African (AFR) AF: 0.632 AC: 26216 AN: 41454

American (AMR) AF: 0.672 AC: 10264 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.660 AC: 2290 AN: 3470

East Asian (EAS) AF: 0.566 AC: 2928 AN: 5176

South Asian (SAS) AF: 0.617 AC: 2977 AN: 4822

European-Finnish (FIN) AF: 0.560 AC: 5902 AN: 10546

Middle Eastern (MID) AF: 0.541 AC: 158 AN: 292

European-Non Finnish (NFE) AF: 0.624 AC: 42396 AN: 67954

Other (OTH) AF: 0.611 AC: 1293 AN: 2116

Alfa AF: 0.616 Hom.: 32035

Bravo AF: 0.631

Asia WGS AF: 0.646 AC: 2244 AN: 3470

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.60
DANN	Benign	0.32
PhyloP100		-0.28
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: rs1570054; hg19: chr6-137101726;