6-136792541-CCGCCGCGCCGCGCCGCGCCG-CCGCCGCGCCGCGCCG

Position:

• chr6-136792541-CCGCCGCGCCGCGCCGCGCCG-CCGCCGCGCCGCGCCG

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BA1

The ENST00000698928.1(MAP3K5):​c.96+99_96+103del 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 ENST00000698928.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.00

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

Verdict is Benign. Variant got -8 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MAP3K5	XM_011535839.4	c.96+99_96+103del		intron_variant			XP_011534141.2
MAP3K5	XM_017010872.2	c.96+99_96+103del		intron_variant			XP_016866361.1
MAP3K5	XM_017010873.2	c.96+99_96+103del		intron_variant			XP_016866362.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAP3K5	ENST00000698928.1	c.96+99_96+103del		intron_variant				ENSP00000514039

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

Gnomad4 AFR exome AF: 0.135

Gnomad4 AMR exome AF: 0.273

Gnomad4 ASJ exome AF: 0.200

Gnomad4 EAS exome AF: 0.208

Gnomad4 SAS exome AF: 0.165

Gnomad4 FIN exome AF: 0.375

Gnomad4 NFE exome AF: 0.189

Gnomad4 OTH exome AF: 0.180

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

Gnomad4 AFR AF: 0.639

Gnomad4 AMR AF: 0.677

Gnomad4 ASJ AF: 0.643

Gnomad4 EAS AF: 0.526

Gnomad4 SAS AF: 0.552

Gnomad4 FIN AF: 0.556

Gnomad4 NFE AF: 0.617

Gnomad4 OTH AF: 0.608

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs5880308; hg19: chr6-137113679;