rs2076262

Variant names:

• chr6-136592079-T-C
• rs2076262
• NM_005923.4:c.3225+94A>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.3225+94A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0429 in 1,206,166 control chromosomes in the GnomAD database, including 4,771 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 0.10 (1848 hom., cov: 32)
  • Exomes 𝑓: 0.034 (2923 hom.)
• Consequence: MAP3K5 NM_005923.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.613
• Publications: 1 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=-0.91).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.258 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAP3K5	NM_005923.4	c.3225+94A>G		intron_variant	Intron 23 of 29	ENST00000359015.5	NP_005914.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAP3K5	ENST00000359015.5	c.3225+94A>G		intron_variant	Intron 23 of 29	1	NM_005923.4	ENSP00000351908.4
MAP3K5	ENST00000698928.1	c.3552+94A>G		intron_variant	Intron 24 of 30			ENSP00000514039.1

Frequencies

GnomAD3 genomes AF: 0.104 AC: 15881 AN: 152122 Hom.: 1837 Cov.: 32

Gnomad AFR AF: 0.261

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.140

Gnomad ASJ AF: 0.0331

Gnomad EAS AF: 0.256

Gnomad SAS AF: 0.0387

Gnomad FIN AF: 0.0141

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0134

Gnomad OTH AF: 0.106

GnomAD4 exome AF: 0.0339 AC: 35748 AN: 1053926 Hom.: 2923 AF XY: 0.0324 AC XY: 17021 AN XY: 525188

African (AFR) AF: 0.267 AC: 6464 AN: 24170

American (AMR) AF: 0.176 AC: 4288 AN: 24326

Ashkenazi Jewish (ASJ) AF: 0.0349 AC: 611 AN: 17524

East Asian (EAS) AF: 0.275 AC: 10040 AN: 36506

South Asian (SAS) AF: 0.0285 AC: 1564 AN: 54840

European-Finnish (FIN) AF: 0.0175 AC: 853 AN: 48712

Middle Eastern (MID) AF: 0.0390 AC: 127 AN: 3254

European-Non Finnish (NFE) AF: 0.0119 AC: 9523 AN: 799296

Other (OTH) AF: 0.0503 AC: 2278 AN: 45298

GnomAD4 genome AF: 0.105 AC: 15943 AN: 152240 Hom.: 1848 Cov.: 32 AF XY: 0.104 AC XY: 7756 AN XY: 74440

African (AFR) AF: 0.262 AC: 10882 AN: 41508

American (AMR) AF: 0.139 AC: 2131 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0331 AC: 115 AN: 3472

East Asian (EAS) AF: 0.256 AC: 1321 AN: 5168

South Asian (SAS) AF: 0.0389 AC: 188 AN: 4828

European-Finnish (FIN) AF: 0.0141 AC: 150 AN: 10622

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.0134 AC: 912 AN: 68024

Other (OTH) AF: 0.111 AC: 234 AN: 2116

Alfa AF: 0.0399 Hom.: 260

Bravo AF: 0.123

Asia WGS AF: 0.181 AC: 629 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.20
DANN	Benign	0.37
PhyloP100		-0.61
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: rs2076262; hg19: chr6-136913217;