NM_005923.4:c.449-5024T>C

Variant names:

• chr6-136725613-A-G
• rs9373173
• NM_005923.4:c.449-5024T>C

Variant summary

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

The NM_005923.4(MAP3K5):​c.449-5024T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.365 in 152,038 control chromosomes in the GnomAD database, including 12,005 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 0.37 (12005 hom., cov: 32)
• Consequence: MAP3K5 NM_005923.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.43
• Publications: 1 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=-0.94).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.475 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAP3K5	NM_005923.4	c.449-5024T>C		intron_variant	Intron 1 of 29	ENST00000359015.5	NP_005914.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAP3K5	ENST00000359015.5	c.449-5024T>C		intron_variant	Intron 1 of 29	1	NM_005923.4	ENSP00000351908.4
MAP3K5	ENST00000698928.1	c.776-5024T>C		intron_variant	Intron 2 of 30			ENSP00000514039.1

Frequencies

GnomAD3 genomes AF: 0.365 AC: 55512 AN: 151918 Hom.: 12009 Cov.: 32

Gnomad AFR AF: 0.124

Gnomad AMI AF: 0.598

Gnomad AMR AF: 0.362

Gnomad ASJ AF: 0.447

Gnomad EAS AF: 0.450

Gnomad SAS AF: 0.402

Gnomad FIN AF: 0.472

Gnomad MID AF: 0.487

Gnomad NFE AF: 0.479

Gnomad OTH AF: 0.378

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.365 AC: 55519 AN: 152038 Hom.: 12005 Cov.: 32 AF XY: 0.365 AC XY: 27144 AN XY: 74302

African (AFR) AF: 0.124 AC: 5142 AN: 41506

American (AMR) AF: 0.361 AC: 5516 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.447 AC: 1551 AN: 3466

East Asian (EAS) AF: 0.450 AC: 2330 AN: 5174

South Asian (SAS) AF: 0.402 AC: 1939 AN: 4824

European-Finnish (FIN) AF: 0.472 AC: 4982 AN: 10548

Middle Eastern (MID) AF: 0.497 AC: 146 AN: 294

European-Non Finnish (NFE) AF: 0.479 AC: 32570 AN: 67936

Other (OTH) AF: 0.378 AC: 798 AN: 2112

Alfa AF: 0.297 Hom.: 1371

Bravo AF: 0.349

Asia WGS AF: 0.357 AC: 1244 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	4.7
DANN	Benign	0.70
PhyloP100		1.4
Mutation Taster		=100/0	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: rs9373173; hg19: chr6-137046751;