rs4351280

Variant names:

• chr6-136556908-A-G
• rs4351280
• NM_005923.4:c.*850T>C

Your query was ambiguous. Multiple possible variants found:

• chr6-136556908-A-G
• chr6-136556908-A-T

Variant summary

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

The NM_005923.4(MAP3K5):​c.*850T>C variant causes a downstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.209 in 151,976 control chromosomes in the GnomAD database, including 3,935 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 0.21 (3935 hom., cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MAP3K5 NM_005923.4 downstream_gene
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.578
• 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.398 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAP3K5	NM_005923.4	c.*850T>C		downstream_gene_variant		ENST00000359015.5	NP_005914.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAP3K5	ENST00000359015.5	c.*850T>C		downstream_gene_variant		1	NM_005923.4	ENSP00000351908.4
MAP3K5	ENST00000698928.1	c.*850T>C		downstream_gene_variant				ENSP00000514039.1

Frequencies

GnomAD3 genomes AF: 0.209 AC: 31686 AN: 151858 Hom.: 3913 Cov.: 32

Gnomad AFR AF: 0.313

Gnomad AMI AF: 0.294

Gnomad AMR AF: 0.232

Gnomad ASJ AF: 0.149

Gnomad EAS AF: 0.412

Gnomad SAS AF: 0.135

Gnomad FIN AF: 0.113

Gnomad MID AF: 0.142

Gnomad NFE AF: 0.147

Gnomad OTH AF: 0.215

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 2 Hom.: 0 AC XY: 0 AN XY: 0

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 2

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.209 AC: 31761 AN: 151976 Hom.: 3935 Cov.: 32 AF XY: 0.206 AC XY: 15295 AN XY: 74280

African (AFR) AF: 0.314 AC: 12980 AN: 41398

American (AMR) AF: 0.231 AC: 3531 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.149 AC: 517 AN: 3464

East Asian (EAS) AF: 0.412 AC: 2123 AN: 5150

South Asian (SAS) AF: 0.136 AC: 652 AN: 4810

European-Finnish (FIN) AF: 0.113 AC: 1196 AN: 10564

Middle Eastern (MID) AF: 0.136 AC: 40 AN: 294

European-Non Finnish (NFE) AF: 0.147 AC: 9991 AN: 68000

Other (OTH) AF: 0.219 AC: 463 AN: 2110

Alfa AF: 0.178 Hom.: 474

Bravo AF: 0.224

Asia WGS AF: 0.301 AC: 1046 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	8.4
DANN	Benign	0.76
PhyloP100		0.58

Splicing

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

Other links and lift over

dbSNP: rs4351280; hg19: chr6-136878046;