Variant 1-27356496-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_004672.5(MAP3K6):c.3529C>T(p.Arg1177Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,322 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1177H) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

MAP3K6
NM_004672.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.20

Variant links:

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 links:

MAP3K6 (HGNC:):

MAP3K6 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MAP3K6	NM_004672.5 linkuse as main transcript	c.3529C>T	p.Arg1177Cys	missense_variant	26/29	ENST00000357582.3	NP_004663.3	O95382-1
MAP3K6	NM_001297609.2 linkuse as main transcript	c.3505C>T	p.Arg1169Cys	missense_variant	25/28		NP_001284538.1	O95382-3
MAP3K6	XM_047433689.1 linkuse as main transcript	c.3436C>T	p.Arg1146Cys	missense_variant	27/30		XP_047289645.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAP3K6	ENST00000357582.3 linkuse as main transcript	c.3529C>T	p.Arg1177Cys	missense_variant	26/29	1	NM_004672.5	ENSP00000350195.2		O95382-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461322

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

726978

show subpopulations

Gnomad4 AFR exome

AF:

0.0000598

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 04, 2024

The c.3529C>T (p.R1177C) alteration is located in exon 26 (coding exon 26) of the MAP3K6 gene. This alteration results from a C to T substitution at nucleotide position 3529, causing the arginine (R) at amino acid position 1177 to be replaced by a cysteine (C). 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

0.14

BayesDel_addAF

Uncertain

0.090

BayesDel_noAF

Benign

-0.11

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.050

.;T;T

Eigen

Benign

0.10

Eigen_PC

Benign

0.033

FATHMM_MKL

Uncertain

0.80

LIST_S2

Uncertain

0.92

D;.;D

M_CAP

Uncertain

0.11

MetaRNN

Uncertain

0.47

T;T;T

MetaSVM

Benign

-0.83

MutationAssessor

Uncertain

2.6

.;M;M

PrimateAI

Uncertain

0.50

PROVEAN

Benign

-1.4

N;N;N

REVEL

Benign

0.20

Sift

Uncertain

0.011

D;D;D

Sift4G

Benign

0.091

T;T;T

Polyphen

1.0

D;D;D

Vest4

0.54

MutPred

0.36

.;Loss of MoRF binding (P = 0.0093);Loss of MoRF binding (P = 0.0093);

MVP

0.51

MPC

1.1

ClinPred

0.92

GERP RS

3.5

Varity_R

0.088

gMVP

0.38

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over