rs9376221

Positions:

• chr6-136671241-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005923.4(MAP3K5):​c.1254-1846A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.145 in 152,186 control chromosomes in the GnomAD database, including 2,230 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 0.14 (2230 hom., cov: 32)
• Consequence: MAP3K5 NM_005923.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.147

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

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.273 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MAP3K5	NM_005923.4	c.1254-1846A>G		intron_variant		ENST00000359015.5	NP_005914.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAP3K5	ENST00000359015.5	c.1254-1846A>G		intron_variant		1	NM_005923.4	ENSP00000351908.4
MAP3K5	ENST00000698928.1	c.1581-1846A>G		intron_variant				ENSP00000514039.1

Frequencies

GnomAD3 genomes AF: 0.145 AC: 22012 AN: 152068 Hom.: 2225 Cov.: 32

Gnomad AFR AF: 0.277

Gnomad AMI AF: 0.106

Gnomad AMR AF: 0.137

Gnomad ASJ AF: 0.135

Gnomad EAS AF: 0.131

Gnomad SAS AF: 0.0704

Gnomad FIN AF: 0.0506

Gnomad MID AF: 0.237

Gnomad NFE AF: 0.0865

Gnomad OTH AF: 0.172

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

GnomAD4 genome AF: 0.145 AC: 22025 AN: 152186 Hom.: 2230 Cov.: 32 AF XY: 0.143 AC XY: 10619 AN XY: 74400

Gnomad4 AFR AF: 0.277

Gnomad4 AMR AF: 0.137

Gnomad4 ASJ AF: 0.135

Gnomad4 EAS AF: 0.132

Gnomad4 SAS AF: 0.0698

Gnomad4 FIN AF: 0.0506

Gnomad4 NFE AF: 0.0864

Gnomad4 OTH AF: 0.170

Alfa AF: 0.0976 Hom.: 1609

Bravo AF: 0.161

Asia WGS AF: 0.0960 AC: 332 AN: 3470

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	2.1
DANN	Benign	0.59

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

Publications

LitVar

Other links and lift over

dbSNP: rs9376221; hg19: chr6-136992379;