chr6-136583695-T-C

Variant names:

• chr6-136583695-T-C
• NM_005923.4:c.3271A>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_005923.4(MAP3K5):​c.3271A>G​(p.Ile1091Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MAP3K5 NM_005923.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.976
• Publications: 0 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: Likely_benign. The variant received -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.056885302).
• BP6: Variant 6-136583695-T-C is Benign according to our data. Variant chr6-136583695-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 2552631.Status of the report is criteria_provided_single_submitter, 1 stars.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAP3K5	NM_005923.4	MANE Select	c.3271A>G	p.Ile1091Val	missense	Exon 24 of 30	NP_005914.1	Q99683-1
	MAP3K5	NM_001438058.1		c.3598A>G	p.Ile1200Val	missense	Exon 25 of 31	NP_001424987.1	A0A8V8TMH5
	MAP3K5	NM_001438579.1		c.2689A>G	p.Ile897Val	missense	Exon 23 of 29	NP_001425508.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAP3K5	ENST00000359015.5	TSL:1 MANE Select	c.3271A>G	p.Ile1091Val	missense	Exon 24 of 30	ENSP00000351908.4	Q99683-1
	MAP3K5	ENST00000698928.1		c.3598A>G	p.Ile1200Val	missense	Exon 25 of 31	ENSP00000514039.1	A0A8V8TMH5
	MAP3K5	ENST00000954598.1		c.3340A>G	p.Ile1114Val	missense	Exon 24 of 30	ENSP00000624657.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.058
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	4.1
DANN	Uncertain	0.98
DEOGEN2	Benign	0.23	T
Eigen	Benign	-0.74
Eigen_PC	Benign	-0.62
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.0099	T
MetaRNN	Benign	0.057	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.17	N
PhyloP100		0.98
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.48	N
REVEL	Benign	0.056
Sift	Benign	0.40	T
Sift4G	Benign	0.43	T
Polyphen		0.0	B
Vest4		0.077
MutPred		0.25		Loss of loop (P = 0.0804)
MVP		0.28
MPC		0.33
ClinPred		0.18	T
GERP RS		0.92
Varity_R		0.020
gMVP		0.12
Mutation Taster		=91/9	polymorphism

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

hg19: chr6-136904833;