6-136792541-CCGCCGCGCCGCGCCGCGCCG-CCGCCG

Variant names:

• chr6-136792541-CCGCCGCGCCGCGCCG-C
• rs5880308
• NM_001438058.1:c.96+89_96+103delCGGCGCGGCGCGGCG

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_001438058.1(MAP3K5):​c.96+89_96+103delCGGCGCGGCGCGGCG variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000968 in 165,256 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000074 (0 hom., cov: 0)
  • Exomes 𝑓: 0.00031 (0 hom.)
• Consequence: MAP3K5 NM_001438058.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.332
• 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: Likely_benign. The variant received -4 ACMG points.

• BS2: High AC in GnomAd4 at 11 AD gene.

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+89_96+103delCGGCGCGGCGCGGCG		intron	N/A	NP_001424987.1
	MAP3K5	NM_005923.4	MANE Select	c.-399_-385delCGGCGCGGCGCGGCG		upstream_gene	N/A	NP_005914.1
	MAP3K5	NM_001438579.1		c.-841_-827delCGGCGCGGCGCGGCG		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+89_96+103delCGGCGCGGCGCGGCG		intron	N/A	ENSP00000514039.1
	MAP3K5	ENST00000359015.5	TSL:1 MANE Select	c.-399_-385delCGGCGCGGCGCGGCG		upstream_gene	N/A	ENSP00000351908.4
	MAP3K5	ENST00000954598.1		c.-399_-385delCGGCGCGGCGCGGCG		upstream_gene	N/A	ENSP00000624657.1

Frequencies

GnomAD3 genomes AF: 0.0000738 AC: 11 AN: 148982 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000123

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000663

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000209

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000598

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000309 AC: 5 AN: 16164 Hom.: 0 AF XY: 0.000504 AC XY: 4 AN XY: 7930

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 266

American (AMR) AF: 0.00 AC: 0 AN: 22

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 90

East Asian (EAS) AF: 0.00 AC: 0 AN: 96

South Asian (SAS) AF: 0.00203 AC: 1 AN: 492

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 42

European-Non Finnish (NFE) AF: 0.000274 AC: 4 AN: 14610

Other (OTH) AF: 0.00 AC: 0 AN: 538

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00271587), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000738 AC: 11 AN: 149092 Hom.: 0 Cov.: 0 AF XY: 0.0000550 AC XY: 4 AN XY: 72714

African (AFR) AF: 0.000123 AC: 5 AN: 40736

American (AMR) AF: 0.0000662 AC: 1 AN: 15108

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3446

East Asian (EAS) AF: 0.00 AC: 0 AN: 4912

South Asian (SAS) AF: 0.000209 AC: 1 AN: 4778

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9930

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.0000598 AC: 4 AN: 66930

Other (OTH) AF: 0.00 AC: 0 AN: 2070

Alfa AF: 0.00 Hom.: 806

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.33

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;