1-27356436-G-C

Position:

• chr1-27356436-G-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_004672.5(MAP3K6):​c.3589C>G​(p.Arg1197Gly) 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. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: MAP3K6 NM_004672.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0930

Genes affected

MAP3K6 (HGNC:6858): (mitogen-activated protein kinase kinase kinase 6) This gene encodes a serine/threonine protein kinase that forms a component of protein kinase-mediated signal transduction cascades. The encoded kinase participates in the regulation of vascular endothelial growth factor (VEGF) expression. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2014]

MAP3K6 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06427637).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MAP3K6	NM_004672.5	c.3589C>G	p.Arg1197Gly	missense_variant	26/29	ENST00000357582.3	NP_004663.3
MAP3K6	NM_001297609.2	c.3565C>G	p.Arg1189Gly	missense_variant	25/28		NP_001284538.1
MAP3K6	XM_047433689.1	c.3496C>G	p.Arg1166Gly	missense_variant	27/30		XP_047289645.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAP3K6	ENST00000357582.3	c.3589C>G	p.Arg1197Gly	missense_variant	26/29	1	NM_004672.5	ENSP00000350195.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 15, 2023

The c.3589C>G (p.R1197G) alteration is located in exon 26 (coding exon 26) of the MAP3K6 gene. This alteration results from a C to G substitution at nucleotide position 3589, causing the arginine (R) at amino acid position 1197 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	14
DANN	Benign	0.92
DEOGEN2	Benign	0.044	.;T;T
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.68
FATHMM_MKL	Benign	0.063	N
LIST_S2	Benign	0.54	T;.;T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.064	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	.;L;L
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-1.7	N;N;N
REVEL	Benign	0.078
Sift	Benign	0.25	T;T;T
Sift4G	Benign	0.11	T;T;T
Polyphen		0.0010	B;B;B
Vest4		0.19
MutPred		0.32		.;Loss of MoRF binding (P = 0.0107);Loss of MoRF binding (P = 0.0107);
MVP		0.35
MPC		0.40
ClinPred		0.064	T
GERP RS		3.5
Varity_R		0.057
gMVP		0.27

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-27682927;