6-136791495-A-G

Variant names:

• chr6-136791495-A-G
• rs3734552
• NM_005923.4:c.448+215T>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+215T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.663 in 152,018 control chromosomes in the GnomAD database, including 33,906 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 0.66 (33906 hom., cov: 30)
• Consequence: MAP3K5 NM_005923.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.48
• Publications: 5 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=-0.86).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.77 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAP3K5	NM_005923.4	c.448+215T>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+215T>C		intron_variant	Intron 1 of 29	1	NM_005923.4	ENSP00000351908.4
MAP3K5	ENST00000698928.1	c.775+215T>C		intron_variant	Intron 2 of 30			ENSP00000514039.1

Frequencies

GnomAD3 genomes AF: 0.663 AC: 100765 AN: 151900 Hom.: 33873 Cov.: 30

Gnomad AFR AF: 0.777

Gnomad AMI AF: 0.477

Gnomad AMR AF: 0.691

Gnomad ASJ AF: 0.647

Gnomad EAS AF: 0.565

Gnomad SAS AF: 0.612

Gnomad FIN AF: 0.554

Gnomad MID AF: 0.545

Gnomad NFE AF: 0.621

Gnomad OTH AF: 0.648

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

GnomAD4 genome AF: 0.663 AC: 100852 AN: 152018 Hom.: 33906 Cov.: 30 AF XY: 0.660 AC XY: 49031 AN XY: 74284

African (AFR) AF: 0.777 AC: 32198 AN: 41458

American (AMR) AF: 0.691 AC: 10573 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.647 AC: 2245 AN: 3472

East Asian (EAS) AF: 0.564 AC: 2907 AN: 5150

South Asian (SAS) AF: 0.612 AC: 2948 AN: 4818

European-Finnish (FIN) AF: 0.554 AC: 5843 AN: 10556

Middle Eastern (MID) AF: 0.534 AC: 156 AN: 292

European-Non Finnish (NFE) AF: 0.621 AC: 42176 AN: 67952

Other (OTH) AF: 0.649 AC: 1371 AN: 2112

Alfa AF: 0.650 Hom.: 4700

Bravo AF: 0.677

Asia WGS AF: 0.648 AC: 2256 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	4.4
DANN	Benign	0.73
PhyloP100		-1.5
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: rs3734552; hg19: chr6-137112633;