6-136622925-A-G

Variant names:

• chr6-136622925-A-G
• rs3765258
• NM_005923.4:c.2073T>C

Variant summary

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

The NM_005923.4(MAP3K5):​c.2073T>C​(p.Tyr691Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0298 in 1,603,288 control chromosomes in the GnomAD database, including 4,644 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 0.094 (1704 hom., cov: 32)
  • Exomes 𝑓: 0.023 (2940 hom.)
• Consequence: MAP3K5 NM_005923.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.55
• 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]

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.26 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.2073T>C	p.Tyr691Tyr	synonymous	Exon 15 of 30	NP_005914.1
	MAP3K5	NM_001438058.1		c.2400T>C	p.Tyr800Tyr	synonymous	Exon 16 of 31	NP_001424987.1
	MAP3K5	NM_001438579.1		c.1491T>C	p.Tyr497Tyr	synonymous	Exon 14 of 29	NP_001425508.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAP3K5	ENST00000359015.5	TSL:1 MANE Select	c.2073T>C	p.Tyr691Tyr	synonymous	Exon 15 of 30	ENSP00000351908.4
	MAP3K5	ENST00000698928.1		c.2400T>C	p.Tyr800Tyr	synonymous	Exon 16 of 31	ENSP00000514039.1

Frequencies

GnomAD3 genomes AF: 0.0941 AC: 14277 AN: 151780 Hom.: 1687 Cov.: 32

Gnomad AFR AF: 0.263

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0980

Gnomad ASJ AF: 0.00605

Gnomad EAS AF: 0.232

Gnomad SAS AF: 0.0213

Gnomad FIN AF: 0.00616

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.00518

Gnomad OTH AF: 0.0817

GnomAD2 exomes AF: 0.0577 AC: 14500 AN: 251412 AF XY: 0.0472

Gnomad AFR exome AF: 0.269

Gnomad AMR exome AF: 0.130

Gnomad ASJ exome AF: 0.00694

Gnomad EAS exome AF: 0.227

Gnomad FIN exome AF: 0.00638

Gnomad NFE exome AF: 0.00477

Gnomad OTH exome AF: 0.0349

GnomAD4 exome AF: 0.0230 AC: 33435 AN: 1451390 Hom.: 2940 Cov.: 32 AF XY: 0.0215 AC XY: 15495 AN XY: 722272

African (AFR) AF: 0.276 AC: 9169 AN: 33268

American (AMR) AF: 0.127 AC: 5646 AN: 44564

Ashkenazi Jewish (ASJ) AF: 0.00656 AC: 170 AN: 25902

East Asian (EAS) AF: 0.243 AC: 9554 AN: 39314

South Asian (SAS) AF: 0.0160 AC: 1374 AN: 86072

European-Finnish (FIN) AF: 0.00619 AC: 328 AN: 52958

Middle Eastern (MID) AF: 0.0309 AC: 177 AN: 5724

European-Non Finnish (NFE) AF: 0.00430 AC: 4746 AN: 1103688

Other (OTH) AF: 0.0379 AC: 2271 AN: 59900

GnomAD4 genome AF: 0.0945 AC: 14348 AN: 151898 Hom.: 1704 Cov.: 32 AF XY: 0.0939 AC XY: 6976 AN XY: 74276

African (AFR) AF: 0.264 AC: 10931 AN: 41452

American (AMR) AF: 0.0983 AC: 1500 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.00605 AC: 21 AN: 3470

East Asian (EAS) AF: 0.233 AC: 1193 AN: 5130

South Asian (SAS) AF: 0.0207 AC: 99 AN: 4778

European-Finnish (FIN) AF: 0.00616 AC: 65 AN: 10560

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.00517 AC: 351 AN: 67928

Other (OTH) AF: 0.0851 AC: 180 AN: 2114

Alfa AF: 0.0370 Hom.: 2742

Bravo AF: 0.112

Asia WGS AF: 0.140 AC: 486 AN: 3478

EpiCase AF: 0.00436

EpiControl AF: 0.00427

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.054
DANN	Benign	0.34
PhyloP100		-1.6
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: rs3765258; hg19: chr6-136944063;