6-136669145-T-C

Variant names:

• chr6-136669145-T-C
• rs3765259
• NM_005923.4:c.1366+138A>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.1366+138A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.488 in 672,108 control chromosomes in the GnomAD database, including 81,543 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 0.45 (16259 hom., cov: 32)
  • Exomes 𝑓: 0.50 (65284 hom.)
• Consequence: MAP3K5 NM_005923.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.319
• Publications: 10 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=-0.83).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.563 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAP3K5	NM_005923.4	c.1366+138A>G		intron_variant	Intron 8 of 29	ENST00000359015.5	NP_005914.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAP3K5	ENST00000359015.5	c.1366+138A>G		intron_variant	Intron 8 of 29	1	NM_005923.4	ENSP00000351908.4
MAP3K5	ENST00000698928.1	c.1693+138A>G		intron_variant	Intron 9 of 30			ENSP00000514039.1

Frequencies

GnomAD3 genomes AF: 0.453 AC: 68859 AN: 151886 Hom.: 16260 Cov.: 32

Gnomad AFR AF: 0.321

Gnomad AMI AF: 0.400

Gnomad AMR AF: 0.573

Gnomad ASJ AF: 0.490

Gnomad EAS AF: 0.459

Gnomad SAS AF: 0.540

Gnomad FIN AF: 0.423

Gnomad MID AF: 0.503

Gnomad NFE AF: 0.503

Gnomad OTH AF: 0.463

GnomAD4 exome AF: 0.498 AC: 258964 AN: 520104 Hom.: 65284 AF XY: 0.500 AC XY: 140905 AN XY: 281806

African (AFR) AF: 0.318 AC: 4230 AN: 13320

American (AMR) AF: 0.610 AC: 13320 AN: 21838

Ashkenazi Jewish (ASJ) AF: 0.498 AC: 8389 AN: 16842

East Asian (EAS) AF: 0.447 AC: 14519 AN: 32484

South Asian (SAS) AF: 0.534 AC: 29317 AN: 54850

European-Finnish (FIN) AF: 0.433 AC: 18156 AN: 41886

Middle Eastern (MID) AF: 0.463 AC: 1004 AN: 2170

European-Non Finnish (NFE) AF: 0.506 AC: 155906 AN: 308242

Other (OTH) AF: 0.496 AC: 14123 AN: 28472

GnomAD4 genome AF: 0.453 AC: 68869 AN: 152004 Hom.: 16259 Cov.: 32 AF XY: 0.452 AC XY: 33557 AN XY: 74276

African (AFR) AF: 0.321 AC: 13316 AN: 41484

American (AMR) AF: 0.573 AC: 8751 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.490 AC: 1700 AN: 3470

East Asian (EAS) AF: 0.460 AC: 2372 AN: 5160

South Asian (SAS) AF: 0.539 AC: 2598 AN: 4822

European-Finnish (FIN) AF: 0.423 AC: 4457 AN: 10546

Middle Eastern (MID) AF: 0.500 AC: 147 AN: 294

European-Non Finnish (NFE) AF: 0.503 AC: 34196 AN: 67934

Other (OTH) AF: 0.459 AC: 968 AN: 2110

Alfa AF: 0.495 Hom.: 33934

Bravo AF: 0.458

Asia WGS AF: 0.460 AC: 1599 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	4.7
DANN	Benign	0.83
PhyloP100		0.32
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: rs3765259; hg19: chr6-136990283; COSMIC: COSV62892829;