6-136768384-A-G

Variant names:

• chr6-136768384-A-G
• rs9402845
• NM_005923.4:c.448+23326T>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.448+23326T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.574 in 152,048 control chromosomes in the GnomAD database, including 25,485 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 0.57 (25485 hom., cov: 32)
• Consequence: MAP3K5 NM_005923.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.72
• 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=-0.88).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.649 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAP3K5	NM_005923.4	c.448+23326T>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.448+23326T>C		intron_variant	Intron 1 of 29	1	NM_005923.4	ENSP00000351908.4
MAP3K5	ENST00000698928.1	c.775+23326T>C		intron_variant	Intron 2 of 30			ENSP00000514039.1

Frequencies

GnomAD3 genomes AF: 0.574 AC: 87195 AN: 151930 Hom.: 25468 Cov.: 32

Gnomad AFR AF: 0.468

Gnomad AMI AF: 0.479

Gnomad AMR AF: 0.659

Gnomad ASJ AF: 0.649

Gnomad EAS AF: 0.533

Gnomad SAS AF: 0.563

Gnomad FIN AF: 0.543

Gnomad MID AF: 0.541

Gnomad NFE AF: 0.626

Gnomad OTH AF: 0.570

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

GnomAD4 genome AF: 0.574 AC: 87231 AN: 152048 Hom.: 25485 Cov.: 32 AF XY: 0.571 AC XY: 42439 AN XY: 74320

African (AFR) AF: 0.468 AC: 19391 AN: 41450

American (AMR) AF: 0.660 AC: 10087 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.649 AC: 2251 AN: 3470

East Asian (EAS) AF: 0.533 AC: 2756 AN: 5168

South Asian (SAS) AF: 0.563 AC: 2714 AN: 4822

European-Finnish (FIN) AF: 0.543 AC: 5735 AN: 10564

Middle Eastern (MID) AF: 0.531 AC: 156 AN: 294

European-Non Finnish (NFE) AF: 0.625 AC: 42512 AN: 67970

Other (OTH) AF: 0.565 AC: 1193 AN: 2110

Alfa AF: 0.473 Hom.: 1481

Bravo AF: 0.576

Asia WGS AF: 0.553 AC: 1924 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	5.4
DANN	Benign	0.69
PhyloP100		1.7
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: rs9402845; hg19: chr6-137089522;