rs2076262

chr6-136592079-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005923.4(MAP3K5):c.3225+94A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0429 in 1,206,166 control chromosomes in the GnomAD database, including 4,771 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 0.10 (1848 hom., cov: 32)
  • Exomes 𝑓: 0.034 (2923 hom.)
• Consequence: MAP3K5 NM_005923.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.613

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.258 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MAP3K5	NM_005923.4	c.3225+94A>G		intron_variant		ENST00000359015.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAP3K5	ENST00000359015.5	c.3225+94A>G		intron_variant		1	NM_005923.4	P1
MAP3K5	ENST00000698928.1	c.3552+94A>G		intron_variant

Frequencies

GnomAD3 genomes AF: 0.104 AC: 15881 AN: 152122 Hom.: 1837 Cov.: 32

Gnomad AFR AF: 0.261

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.140

Gnomad ASJ AF: 0.0331

Gnomad EAS AF: 0.256

Gnomad SAS AF: 0.0387

Gnomad FIN AF: 0.0141

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0134

Gnomad OTH AF: 0.106

GnomAD4 exome AF: 0.0339 AC: 35748 AN: 1053926 Hom.: 2923 AF XY: 0.0324 AC XY: 17021 AN XY: 525188

Gnomad4 AFR exome AF: 0.267

Gnomad4 AMR exome AF: 0.176

Gnomad4 ASJ exome AF: 0.0349

Gnomad4 EAS exome AF: 0.275

Gnomad4 SAS exome AF: 0.0285

Gnomad4 FIN exome AF: 0.0175

Gnomad4 NFE exome AF: 0.0119

Gnomad4 OTH exome AF: 0.0503

GnomAD4 genome AF: 0.105 AC: 15943 AN: 152240 Hom.: 1848 Cov.: 32 AF XY: 0.104 AC XY: 7756 AN XY: 74440

Gnomad4 AFR AF: 0.262

Gnomad4 AMR AF: 0.139

Gnomad4 ASJ AF: 0.0331

Gnomad4 EAS AF: 0.256

Gnomad4 SAS AF: 0.0389

Gnomad4 FIN AF: 0.0141

Gnomad4 NFE AF: 0.0134

Gnomad4 OTH AF: 0.111

Alfa AF: 0.0385 Hom.: 212

Bravo AF: 0.123

Asia WGS AF: 0.181 AC: 629 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
Cadd	Benign	0.20
Dann	Benign	0.37

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs2076262; hg19: chr6-136913217;