chr6-136792541-CCGCCG-C

Variant names:

• chr6-136792541-CCGCCG-C
• rs5880308
• NM_001438058.1:c.96+99_96+103delCGGCG

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

The NM_001438058.1(MAP3K5):​c.96+99_96+103delCGGCG variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.577 in 165,144 control chromosomes in the GnomAD database, including 29,633 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.62 (28649 hom., cov: 0)
  • Exomes 𝑓: 0.19 (984 hom.)
• Consequence: MAP3K5 NM_001438058.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.00
• Publications: 2 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 -8 ACMG points.

• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.666 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001438058.1. 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_001438058.1		c.96+99_96+103delCGGCG		intron	N/A	NP_001424987.1
	MAP3K5	NM_005923.4	MANE Select	c.-389_-385delCGGCG		upstream_gene	N/A	NP_005914.1
	MAP3K5	NM_001438579.1		c.-831_-827delCGGCG		upstream_gene	N/A	NP_001425508.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAP3K5	ENST00000698928.1		c.96+99_96+103delCGGCG		intron	N/A	ENSP00000514039.1
	MAP3K5	ENST00000359015.5	TSL:1 MANE Select	c.-389_-385delCGGCG		upstream_gene	N/A	ENSP00000351908.4
	MAP3K5	ENST00000954598.1		c.-389_-385delCGGCG		upstream_gene	N/A	ENSP00000624657.1

Frequencies

GnomAD3 genomes AF: 0.620 AC: 92255 AN: 148880 Hom.: 28630 Cov.: 0

Gnomad AFR AF: 0.640

Gnomad AMI AF: 0.473

Gnomad AMR AF: 0.676

Gnomad ASJ AF: 0.643

Gnomad EAS AF: 0.526

Gnomad SAS AF: 0.552

Gnomad FIN AF: 0.556

Gnomad MID AF: 0.542

Gnomad NFE AF: 0.617

Gnomad OTH AF: 0.609

GnomAD4 exome AF: 0.188 AC: 3035 AN: 16154 Hom.: 984 AF XY: 0.197 AC XY: 1560 AN XY: 7922

African (AFR) AF: 0.135 AC: 36 AN: 266

American (AMR) AF: 0.273 AC: 6 AN: 22

Ashkenazi Jewish (ASJ) AF: 0.200 AC: 18 AN: 90

East Asian (EAS) AF: 0.208 AC: 20 AN: 96

South Asian (SAS) AF: 0.165 AC: 81 AN: 492

European-Finnish (FIN) AF: 0.375 AC: 3 AN: 8

Middle Eastern (MID) AF: 0.262 AC: 11 AN: 42

European-Non Finnish (NFE) AF: 0.189 AC: 2763 AN: 14600

Other (OTH) AF: 0.180 AC: 97 AN: 538

GnomAD4 genome AF: 0.620 AC: 92310 AN: 148990 Hom.: 28649 Cov.: 0 AF XY: 0.617 AC XY: 44838 AN XY: 72670

African (AFR) AF: 0.639 AC: 26021 AN: 40702

American (AMR) AF: 0.677 AC: 10220 AN: 15102

Ashkenazi Jewish (ASJ) AF: 0.643 AC: 2214 AN: 3444

East Asian (EAS) AF: 0.526 AC: 2582 AN: 4906

South Asian (SAS) AF: 0.552 AC: 2632 AN: 4766

European-Finnish (FIN) AF: 0.556 AC: 5512 AN: 9922

Middle Eastern (MID) AF: 0.531 AC: 154 AN: 290

European-Non Finnish (NFE) AF: 0.617 AC: 41296 AN: 66900

Other (OTH) AF: 0.608 AC: 1258 AN: 2068

Alfa AF: 0.320 Hom.: 806

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.0
Mutation Taster		=100/0	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs5880308; hg19: chr6-137113679; COSMIC: COSV62889875;