chr6-136641470-T-C

Variant names:

• chr6-136641470-T-C
• rs9385770
• NM_005923.4:c.1838+1050A>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.1838+1050A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.56 in 151,900 control chromosomes in the GnomAD database, including 24,931 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 0.56 (24931 hom., cov: 31)
• Consequence: MAP3K5 NM_005923.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.588
• 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]

MAP3K5-AS1 (HGNC:40358): (MAP3K5 antisense RNA 1)

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 (SAS) allele frequency at 95% confidence interval = 0.692 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAP3K5	NM_005923.4	c.1838+1050A>G		intron_variant	Intron 12 of 29	ENST00000359015.5	NP_005914.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAP3K5	ENST00000359015.5	c.1838+1050A>G		intron_variant	Intron 12 of 29	1	NM_005923.4	ENSP00000351908.4
MAP3K5	ENST00000698928.1	c.2165+1050A>G		intron_variant	Intron 13 of 30			ENSP00000514039.1
MAP3K5-AS1	ENST00000432477.2	n.383+4368T>C		intron_variant	Intron 2 of 2	2

Frequencies

GnomAD3 genomes AF: 0.561 AC: 85108 AN: 151782 Hom.: 24943 Cov.: 31

Gnomad AFR AF: 0.395

Gnomad AMI AF: 0.802

Gnomad AMR AF: 0.566

Gnomad ASJ AF: 0.652

Gnomad EAS AF: 0.555

Gnomad SAS AF: 0.713

Gnomad FIN AF: 0.548

Gnomad MID AF: 0.652

Gnomad NFE AF: 0.643

Gnomad OTH AF: 0.583

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

GnomAD4 genome AF: 0.560 AC: 85108 AN: 151900 Hom.: 24931 Cov.: 31 AF XY: 0.557 AC XY: 41354 AN XY: 74234

African (AFR) AF: 0.395 AC: 16350 AN: 41404

American (AMR) AF: 0.565 AC: 8628 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.652 AC: 2263 AN: 3470

East Asian (EAS) AF: 0.555 AC: 2874 AN: 5180

South Asian (SAS) AF: 0.712 AC: 3434 AN: 4822

European-Finnish (FIN) AF: 0.548 AC: 5749 AN: 10498

Middle Eastern (MID) AF: 0.643 AC: 189 AN: 294

European-Non Finnish (NFE) AF: 0.643 AC: 43682 AN: 67956

Other (OTH) AF: 0.575 AC: 1208 AN: 2102

Alfa AF: 0.593 Hom.: 12354

Bravo AF: 0.550

Asia WGS AF: 0.610 AC: 2122 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.99
DANN	Benign	0.65
PhyloP100		-0.59
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: rs9385770; hg19: chr6-136962608; COSMIC: COSV107447755;