chr6-136774541-G-C

Variant names:

• chr6-136774541-G-C
• rs9321570
• NM_005923.4:c.448+17169C>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.448+17169C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.62 in 152,058 control chromosomes in the GnomAD database, including 29,406 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 0.62 (29406 hom., cov: 32)
• Consequence: MAP3K5 NM_005923.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0210
• Publications: 11 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=-0.96).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.664 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.448+17169C>G		intron	N/A	NP_005914.1
	MAP3K5	NM_001438058.1		c.775+17169C>G		intron	N/A	NP_001424987.1
	MAP3K5	NM_001438579.1		c.6+17169C>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.448+17169C>G		intron	N/A	ENSP00000351908.4
	MAP3K5	ENST00000698928.1		c.775+17169C>G		intron	N/A	ENSP00000514039.1

Frequencies

GnomAD3 genomes AF: 0.620 AC: 94274 AN: 151940 Hom.: 29389 Cov.: 32

Gnomad AFR AF: 0.634

Gnomad AMI AF: 0.478

Gnomad AMR AF: 0.675

Gnomad ASJ AF: 0.657

Gnomad EAS AF: 0.565

Gnomad SAS AF: 0.617

Gnomad FIN AF: 0.531

Gnomad MID AF: 0.551

Gnomad NFE AF: 0.619

Gnomad OTH AF: 0.607

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

GnomAD4 genome AF: 0.620 AC: 94333 AN: 152058 Hom.: 29406 Cov.: 32 AF XY: 0.618 AC XY: 45900 AN XY: 74328

African (AFR) AF: 0.633 AC: 26260 AN: 41470

American (AMR) AF: 0.675 AC: 10324 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.657 AC: 2280 AN: 3468

East Asian (EAS) AF: 0.565 AC: 2925 AN: 5178

South Asian (SAS) AF: 0.617 AC: 2971 AN: 4816

European-Finnish (FIN) AF: 0.531 AC: 5600 AN: 10542

Middle Eastern (MID) AF: 0.541 AC: 159 AN: 294

European-Non Finnish (NFE) AF: 0.619 AC: 42093 AN: 67980

Other (OTH) AF: 0.608 AC: 1286 AN: 2114

Alfa AF: 0.500 Hom.: 1336

Bravo AF: 0.628

Asia WGS AF: 0.644 AC: 2242 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	2.1
DANN	Benign	0.52
PhyloP100		-0.021
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: rs9321570; hg19: chr6-137095679;