6-136712568-T-C

Variant names:

• chr6-136712568-T-C
• rs911185
• NM_005923.4:c.589-7435A>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.589-7435A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.551 in 151,988 control chromosomes in the GnomAD database, including 23,749 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 0.55 (23749 hom., cov: 32)
• Consequence: MAP3K5 NM_005923.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.19
• Publications: 4 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=-0.99).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.671 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAP3K5	NM_005923.4	MANE Select	c.589-7435A>G		intron	N/A	NP_005914.1	Q99683-1
	MAP3K5	NM_001438058.1		c.916-7435A>G		intron	N/A	NP_001424987.1	A0A8V8TMH5
	MAP3K5	NM_001438579.1		c.7-7435A>G		intron	N/A	NP_001425508.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAP3K5	ENST00000359015.5	TSL:1 MANE Select	c.589-7435A>G		intron	N/A	ENSP00000351908.4	Q99683-1
	MAP3K5	ENST00000698928.1		c.916-7435A>G		intron	N/A	ENSP00000514039.1	A0A8V8TMH5
	MAP3K5	ENST00000954598.1		c.589-7435A>G		intron	N/A	ENSP00000624657.1

Frequencies

GnomAD3 genomes AF: 0.551 AC: 83647 AN: 151868 Hom.: 23690 Cov.: 32

Gnomad AFR AF: 0.676

Gnomad AMI AF: 0.677

Gnomad AMR AF: 0.434

Gnomad ASJ AF: 0.467

Gnomad EAS AF: 0.483

Gnomad SAS AF: 0.383

Gnomad FIN AF: 0.582

Gnomad MID AF: 0.516

Gnomad NFE AF: 0.516

Gnomad OTH AF: 0.527

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

GnomAD4 genome AF: 0.551 AC: 83765 AN: 151988 Hom.: 23749 Cov.: 32 AF XY: 0.547 AC XY: 40646 AN XY: 74278

African (AFR) AF: 0.677 AC: 28087 AN: 41464

American (AMR) AF: 0.433 AC: 6602 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.467 AC: 1621 AN: 3472

East Asian (EAS) AF: 0.483 AC: 2502 AN: 5180

South Asian (SAS) AF: 0.384 AC: 1849 AN: 4818

European-Finnish (FIN) AF: 0.582 AC: 6143 AN: 10552

Middle Eastern (MID) AF: 0.524 AC: 154 AN: 294

European-Non Finnish (NFE) AF: 0.516 AC: 35072 AN: 67930

Other (OTH) AF: 0.531 AC: 1120 AN: 2110

Alfa AF: 0.532 Hom.: 3706

Bravo AF: 0.548

Asia WGS AF: 0.456 AC: 1589 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	0.10
DANN	Benign	0.64
PhyloP100		-1.2
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: rs911185; hg19: chr6-137033706;