chr6-136635502-T-A

Variant names:

• chr6-136635502-T-A
• rs7775356
• NM_005923.4:c.2016+1823A>T

Variant summary

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

The NM_005923.4(MAP3K5):​c.2016+1823A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.645 in 151,880 control chromosomes in the GnomAD database, including 31,888 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 0.65 (31888 hom., cov: 31)
• Consequence: MAP3K5 NM_005923.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.21
• Publications: 2 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]

MAP3K5-AS1 (HGNC:40358): (MAP3K5 antisense RNA 1)

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.694 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAP3K5	NM_005923.4	c.2016+1823A>T		intron_variant	Intron 14 of 29	ENST00000359015.5	NP_005914.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAP3K5	ENST00000359015.5	c.2016+1823A>T		intron_variant	Intron 14 of 29	1	NM_005923.4	ENSP00000351908.4
MAP3K5	ENST00000698928.1	c.2343+1823A>T		intron_variant	Intron 15 of 30			ENSP00000514039.1
MAP3K5-AS1	ENST00000432477.2	n.212-1429T>A		intron_variant	Intron 1 of 2	2

Frequencies

GnomAD3 genomes AF: 0.646 AC: 97968 AN: 151762 Hom.: 31870 Cov.: 31

Gnomad AFR AF: 0.685

Gnomad AMI AF: 0.752

Gnomad AMR AF: 0.659

Gnomad ASJ AF: 0.649

Gnomad EAS AF: 0.711

Gnomad SAS AF: 0.716

Gnomad FIN AF: 0.542

Gnomad MID AF: 0.649

Gnomad NFE AF: 0.622

Gnomad OTH AF: 0.660

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

GnomAD4 genome AF: 0.645 AC: 98036 AN: 151880 Hom.: 31888 Cov.: 31 AF XY: 0.643 AC XY: 47718 AN XY: 74196

African (AFR) AF: 0.686 AC: 28385 AN: 41404

American (AMR) AF: 0.659 AC: 10050 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.649 AC: 2249 AN: 3468

East Asian (EAS) AF: 0.711 AC: 3681 AN: 5180

South Asian (SAS) AF: 0.714 AC: 3444 AN: 4822

European-Finnish (FIN) AF: 0.542 AC: 5678 AN: 10484

Middle Eastern (MID) AF: 0.643 AC: 189 AN: 294

European-Non Finnish (NFE) AF: 0.622 AC: 42290 AN: 67944

Other (OTH) AF: 0.655 AC: 1384 AN: 2112

Alfa AF: 0.629 Hom.: 3705

Bravo AF: 0.653

Asia WGS AF: 0.708 AC: 2459 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.28
DANN	Benign	0.35
PhyloP100		-1.2
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: rs7775356; hg19: chr6-136956640;