Variant 1-27356725-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_004672.5(MAP3K6):c.3389C>T(p.Pro1130Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000771 in 1,426,648 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Likely benign (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000077 ( 0 hom. )

Consequence

MAP3K6
NM_004672.5 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -1.06

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 Benign. Variant got -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.028499484).

BP6

Variant 1-27356725-G-A is Benign according to our data. Variant chr1-27356725-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 3293079.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High AC in GnomAdExome4 at 11 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MAP3K6	NM_004672.5 linkuse as main transcript	c.3389C>T	p.Pro1130Leu	missense_variant	25/29	ENST00000357582.3	NP_004663.3	O95382-1
MAP3K6	NM_001297609.2 linkuse as main transcript	c.3365C>T	p.Pro1122Leu	missense_variant	24/28		NP_001284538.1	O95382-3
MAP3K6	XM_047433689.1 linkuse as main transcript	c.3296C>T	p.Pro1099Leu	missense_variant	26/30		XP_047289645.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAP3K6	ENST00000357582.3 linkuse as main transcript	c.3389C>T	p.Pro1130Leu	missense_variant	25/29	1	NM_004672.5	ENSP00000350195.2		O95382-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000455

AC:

AN:

219826

Hom.:

AF XY:

0.0000507

AC XY:

AN XY:

118292

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000572

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000771

AC:

AN:

1426648

Hom.:

Cov.:

AF XY:

0.00000708

AC XY:

AN XY:

706538

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000279

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 19, 2024

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.067

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.57

CADD

Benign

1.9

DANN

Benign

0.80

DEOGEN2

Benign

0.048

.;T;T

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.026

LIST_S2

Benign

0.61

T;.;T

M_CAP

Benign

0.017

MetaRNN

Benign

0.028

T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.69

.;N;N

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.59

N;N;N

REVEL

Benign

0.057

Sift

Benign

0.20

T;T;T

Sift4G

Benign

0.11

T;T;T

Polyphen

0.0010

B;B;B

Vest4

0.056

MutPred

0.19

.;Loss of methylation at K1125 (P = 0.0588);Loss of methylation at K1125 (P = 0.0588);

MVP

0.11

MPC

0.32

ClinPred

0.0085

GERP RS

-4.7

Varity_R

0.024

gMVP

0.16

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.11

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over