NM_005923.4:c.1681-2054G>A

Variant names:

• chr6-136653145-C-T
• rs6904753
• NM_005923.4:c.1681-2054G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005923.4(MAP3K5):​c.1681-2054G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.246 in 151,930 control chromosomes in the GnomAD database, including 5,329 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 0.25 (5329 hom., cov: 32)
• Consequence: MAP3K5 NM_005923.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.365
• Publications: 5 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=-0.93).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.516 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAP3K5	NM_005923.4	c.1681-2054G>A		intron_variant	Intron 10 of 29	ENST00000359015.5	NP_005914.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAP3K5	ENST00000359015.5	c.1681-2054G>A		intron_variant	Intron 10 of 29	1	NM_005923.4	ENSP00000351908.4
MAP3K5	ENST00000698928.1	c.2008-2054G>A		intron_variant	Intron 11 of 30			ENSP00000514039.1

Frequencies

GnomAD3 genomes AF: 0.246 AC: 37356 AN: 151812 Hom.: 5315 Cov.: 32

Gnomad AFR AF: 0.363

Gnomad AMI AF: 0.159

Gnomad AMR AF: 0.232

Gnomad ASJ AF: 0.139

Gnomad EAS AF: 0.533

Gnomad SAS AF: 0.287

Gnomad FIN AF: 0.147

Gnomad MID AF: 0.177

Gnomad NFE AF: 0.176

Gnomad OTH AF: 0.227

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

GnomAD4 genome AF: 0.246 AC: 37412 AN: 151930 Hom.: 5329 Cov.: 32 AF XY: 0.247 AC XY: 18341 AN XY: 74278

African (AFR) AF: 0.364 AC: 15061 AN: 41406

American (AMR) AF: 0.232 AC: 3536 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.139 AC: 481 AN: 3468

East Asian (EAS) AF: 0.532 AC: 2753 AN: 5170

South Asian (SAS) AF: 0.286 AC: 1373 AN: 4802

European-Finnish (FIN) AF: 0.147 AC: 1547 AN: 10542

Middle Eastern (MID) AF: 0.170 AC: 50 AN: 294

European-Non Finnish (NFE) AF: 0.176 AC: 11982 AN: 67958

Other (OTH) AF: 0.230 AC: 484 AN: 2106

Alfa AF: 0.193 Hom.: 5276

Bravo AF: 0.253

Asia WGS AF: 0.378 AC: 1312 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	5.5
DANN	Benign	0.60
PhyloP100		0.36
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: rs6904753; hg19: chr6-136974283;