chr6-136656430-T-C

Variant names:

• chr6-136656430-T-C
• rs2076260
• NM_005923.4:c.1557A>G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_005923.4(MAP3K5):​c.1557A>G​(p.Leu519Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.216 in 1,596,572 control chromosomes in the GnomAD database, including 49,900 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 0.33 (11903 hom., cov: 32)
  • Exomes 𝑓: 0.20 (37997 hom.)
• Consequence: MAP3K5 NM_005923.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.59

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP7: Synonymous conserved (PhyloP=1.59 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.652 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAP3K5	NM_005923.4	c.1557A>G	p.Leu519Leu	synonymous_variant	Exon 10 of 30	ENST00000359015.5	NP_005914.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAP3K5	ENST00000359015.5	c.1557A>G	p.Leu519Leu	synonymous_variant	Exon 10 of 30	1	NM_005923.4	ENSP00000351908.4
MAP3K5	ENST00000698928.1	c.1884A>G	p.Leu628Leu	synonymous_variant	Exon 11 of 31			ENSP00000514039.1

Frequencies

GnomAD3 genomes AF: 0.333 AC: 50562 AN: 151888 Hom.: 11866 Cov.: 32

Gnomad AFR AF: 0.658

Gnomad AMI AF: 0.161

Gnomad AMR AF: 0.269

Gnomad ASJ AF: 0.161

Gnomad EAS AF: 0.538

Gnomad SAS AF: 0.297

Gnomad FIN AF: 0.146

Gnomad MID AF: 0.197

Gnomad NFE AF: 0.179

Gnomad OTH AF: 0.296

GnomAD3 exomes AF: 0.265 AC: 63000 AN: 237566 Hom.: 11198 AF XY: 0.255 AC XY: 32719 AN XY: 128518

Gnomad AFR exome AF: 0.667

Gnomad AMR exome AF: 0.305

Gnomad ASJ exome AF: 0.154

Gnomad EAS exome AF: 0.571

Gnomad SAS exome AF: 0.296

Gnomad FIN exome AF: 0.148

Gnomad NFE exome AF: 0.172

Gnomad OTH exome AF: 0.219

GnomAD4 exome AF: 0.204 AC: 294842 AN: 1444568 Hom.: 37997 Cov.: 30 AF XY: 0.205 AC XY: 147313 AN XY: 718634

Gnomad4 AFR exome AF: 0.674

Gnomad4 AMR exome AF: 0.296

Gnomad4 ASJ exome AF: 0.151

Gnomad4 EAS exome AF: 0.546

Gnomad4 SAS exome AF: 0.289

Gnomad4 FIN exome AF: 0.153

Gnomad4 NFE exome AF: 0.171

Gnomad4 OTH exome AF: 0.225

GnomAD4 genome AF: 0.333 AC: 50656 AN: 152004 Hom.: 11903 Cov.: 32 AF XY: 0.330 AC XY: 24555 AN XY: 74308

Gnomad4 AFR AF: 0.658

Gnomad4 AMR AF: 0.269

Gnomad4 ASJ AF: 0.161

Gnomad4 EAS AF: 0.538

Gnomad4 SAS AF: 0.296

Gnomad4 FIN AF: 0.146

Gnomad4 NFE AF: 0.179

Gnomad4 OTH AF: 0.299

Alfa AF: 0.229 Hom.: 4110

Bravo AF: 0.354

Asia WGS AF: 0.409 AC: 1420 AN: 3478

EpiCase AF: 0.171

EpiControl AF: 0.163

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	10
DANN	Benign	0.85

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: rs2076260; hg19: chr6-136977568; COSMIC: COSV62887871;