6-136588104-T-C

Variant names:

• chr6-136588104-T-C
• rs2327743
• NM_005923.4:c.3225+4069A>G

Variant summary

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

The NM_005923.4(MAP3K5):​c.3225+4069A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.284 in 152,052 control chromosomes in the GnomAD database, including 8,590 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 0.28 (8590 hom., cov: 32)
• Consequence: MAP3K5 NM_005923.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0450
• 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=-0.88).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.55 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005923.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAP3K5	NM_005923.4	MANE Select	c.3225+4069A>G		intron	N/A	NP_005914.1
	MAP3K5	NM_001438058.1		c.3552+4069A>G		intron	N/A	NP_001424987.1
	MAP3K5	NM_001438579.1		c.2643+4069A>G		intron	N/A	NP_001425508.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAP3K5	ENST00000359015.5	TSL:1 MANE Select	c.3225+4069A>G		intron	N/A	ENSP00000351908.4
	MAP3K5	ENST00000698928.1		c.3552+4069A>G		intron	N/A	ENSP00000514039.1

Frequencies

GnomAD3 genomes AF: 0.284 AC: 43096 AN: 151934 Hom.: 8553 Cov.: 32

Gnomad AFR AF: 0.556

Gnomad AMI AF: 0.294

Gnomad AMR AF: 0.264

Gnomad ASJ AF: 0.151

Gnomad EAS AF: 0.439

Gnomad SAS AF: 0.140

Gnomad FIN AF: 0.117

Gnomad MID AF: 0.187

Gnomad NFE AF: 0.154

Gnomad OTH AF: 0.273

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

GnomAD4 genome AF: 0.284 AC: 43191 AN: 152052 Hom.: 8590 Cov.: 32 AF XY: 0.280 AC XY: 20788 AN XY: 74320

African (AFR) AF: 0.556 AC: 23057 AN: 41438

American (AMR) AF: 0.264 AC: 4028 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.151 AC: 524 AN: 3468

East Asian (EAS) AF: 0.439 AC: 2263 AN: 5154

South Asian (SAS) AF: 0.140 AC: 674 AN: 4826

European-Finnish (FIN) AF: 0.117 AC: 1242 AN: 10580

Middle Eastern (MID) AF: 0.184 AC: 54 AN: 294

European-Non Finnish (NFE) AF: 0.154 AC: 10499 AN: 68002

Other (OTH) AF: 0.277 AC: 582 AN: 2104

Alfa AF: 0.186 Hom.: 1998

Bravo AF: 0.310

Asia WGS AF: 0.322 AC: 1123 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	6.4
DANN	Benign	0.79
PhyloP100		0.045
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: rs2327743; hg19: chr6-136909242;