6-136792541-CCGCCGCGCCGCGCCGCGCCG-CCGCCGCGCCG

Position:

• chr6-136792541-CCGCCGCGCCGCGCCGCGCCG-CCGCCGCGCCG

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The ENST00000698928.1(MAP3K5):​c.96+94_96+103del variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000847 in 165,254 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00091 (0 hom., cov: 0)
  • Exomes 𝑓: 0.00025 (0 hom.)
• Consequence: MAP3K5 ENST00000698928.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.332

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 Likely_benign. Variant got -4 ACMG points.

• BS2: High AC in GnomAd4 at 136 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MAP3K5	XM_011535839.4	c.96+94_96+103del		intron_variant			XP_011534141.2
MAP3K5	XM_017010872.2	c.96+94_96+103del		intron_variant			XP_016866361.1
MAP3K5	XM_017010873.2	c.96+94_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+94_96+103del		intron_variant				ENSP00000514039

Frequencies

GnomAD3 genomes AF: 0.000926 AC: 138 AN: 148982 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00192

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000663

Gnomad ASJ AF: 0.00696

Gnomad EAS AF: 0.000406

Gnomad SAS AF: 0.00146

Gnomad FIN AF: 0.000101

Gnomad MID AF: 0.00968

Gnomad NFE AF: 0.000194

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000247 AC: 4 AN: 16162 Hom.: 0 AF XY: 0.000378 AC XY: 3 AN XY: 7928

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000274

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.000912 AC: 136 AN: 149092 Hom.: 0 Cov.: 0 AF XY: 0.00109 AC XY: 79 AN XY: 72712

Gnomad4 AFR AF: 0.00189

Gnomad4 AMR AF: 0.000662

Gnomad4 ASJ AF: 0.00696

Gnomad4 EAS AF: 0.000407

Gnomad4 SAS AF: 0.00147

Gnomad4 FIN AF: 0.000101

Gnomad4 NFE AF: 0.000194

Gnomad4 OTH AF: 0.00

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;