rs4896219

Variant names:

• chr6-136758404-C-A
• rs4896219
• NM_005923.4:c.448+33306G>T

Your query was ambiguous. Multiple possible variants found:

• chr6-136758404-C-A
• chr6-136758404-C-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+33306G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.402 in 152,176 control chromosomes in the GnomAD database, including 14,012 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 0.40 (14012 hom., cov: 33)
• Consequence: MAP3K5 NM_005923.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.539
• Publications: 13 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]

ENSG00000296207 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.509 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+33306G>T		intron	N/A	NP_005914.1
	MAP3K5	NM_001438058.1		c.775+33306G>T		intron	N/A	NP_001424987.1
	MAP3K5	NM_001438579.1		c.6+33306G>T		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+33306G>T		intron	N/A	ENSP00000351908.4
	MAP3K5	ENST00000698928.1		c.775+33306G>T		intron	N/A	ENSP00000514039.1
	ENSG00000296207	ENST00000737288.1		n.246+1628C>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.402 AC: 61180 AN: 152056 Hom.: 14008 Cov.: 33

Gnomad AFR AF: 0.173

Gnomad AMI AF: 0.559

Gnomad AMR AF: 0.394

Gnomad ASJ AF: 0.480

Gnomad EAS AF: 0.462

Gnomad SAS AF: 0.447

Gnomad FIN AF: 0.505

Gnomad MID AF: 0.525

Gnomad NFE AF: 0.513

Gnomad OTH AF: 0.417

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

GnomAD4 genome AF: 0.402 AC: 61198 AN: 152176 Hom.: 14012 Cov.: 33 AF XY: 0.402 AC XY: 29933 AN XY: 74394

African (AFR) AF: 0.173 AC: 7179 AN: 41542

American (AMR) AF: 0.393 AC: 6013 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.480 AC: 1663 AN: 3468

East Asian (EAS) AF: 0.462 AC: 2390 AN: 5178

South Asian (SAS) AF: 0.448 AC: 2158 AN: 4822

European-Finnish (FIN) AF: 0.505 AC: 5334 AN: 10568

Middle Eastern (MID) AF: 0.537 AC: 158 AN: 294

European-Non Finnish (NFE) AF: 0.513 AC: 34903 AN: 67994

Other (OTH) AF: 0.422 AC: 890 AN: 2108

Alfa AF: 0.473 Hom.: 56703

Bravo AF: 0.386

Asia WGS AF: 0.428 AC: 1488 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.16
DANN	Benign	0.31
PhyloP100		-0.54
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: rs4896219; hg19: chr6-137079542;