6-136656430-T-C

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 20 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 -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

GnomAD2 exomes AF: 0.265 AC: 63000 AN: 237566 AF XY: 0.255

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 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

African (AFR) AF: 0.674 AC: 21826 AN: 32398

American (AMR) AF: 0.296 AC: 12110 AN: 40890

Ashkenazi Jewish (ASJ) AF: 0.151 AC: 3826 AN: 25298

East Asian (EAS) AF: 0.546 AC: 21616 AN: 39588

South Asian (SAS) AF: 0.289 AC: 24149 AN: 83678

European-Finnish (FIN) AF: 0.153 AC: 8138 AN: 53098

Middle Eastern (MID) AF: 0.206 AC: 1172 AN: 5694

European-Non Finnish (NFE) AF: 0.171 AC: 188593 AN: 1104280

Other (OTH) AF: 0.225 AC: 13412 AN: 59644

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

African (AFR) AF: 0.658 AC: 27273 AN: 41418

American (AMR) AF: 0.269 AC: 4105 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.161 AC: 559 AN: 3472

East Asian (EAS) AF: 0.538 AC: 2767 AN: 5146

South Asian (SAS) AF: 0.296 AC: 1425 AN: 4816

European-Finnish (FIN) AF: 0.146 AC: 1549 AN: 10590

Middle Eastern (MID) AF: 0.195 AC: 57 AN: 292

European-Non Finnish (NFE) AF: 0.179 AC: 12143 AN: 67970

Other (OTH) AF: 0.299 AC: 631 AN: 2110

Alfa AF: 0.241 Hom.: 6750

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
PhyloP100		1.6
Mutation Taster		=280/20	polymorphism (auto)

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

Other links and lift over

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