chr1-27360975-G-T

Position:

chr1-27360975-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_004672.5(MAP3K6):c.1866C>A(p.Asn622Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.267 in 1,605,104 control chromosomes in the GnomAD database, including 61,678 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.21 ( 4302 hom., cov: 33)

Exomes 𝑓: 0.27 ( 57376 hom. )

Consequence

MAP3K6
NM_004672.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.183

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0039737225).

BP6

Variant 1-27360975-G-T is Benign according to our data. Variant chr1-27360975-G-T is described in ClinVar as [Benign]. Clinvar id is 403071.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.299 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MAP3K6	NM_004672.5 linkuse as main transcript	c.1866C>A	p.Asn622Lys	missense_variant	14/29	ENST00000357582.3	NP_004663.3	O95382-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
MAP3K6	ENST00000357582.3 linkuse as main transcript	c.1866C>A	p.Asn622Lys	missense_variant	14/29	1	NM_004672.5	ENSP00000350195.2	O95382-1
MAP3K6	ENST00000374040.7 linkuse as main transcript	c.1842C>A	p.Asn614Lys	missense_variant	13/28	1		ENSP00000363152.2	O95382-3
MAP3K6	ENST00000493901.6 linkuse as main transcript	n.1470C>A		non_coding_transcript_exon_variant	12/27	5
MAP3K6	ENST00000671291.1 linkuse as main transcript	n.700C>A		non_coding_transcript_exon_variant	7/20

Frequencies

GnomAD3 genomes

AF:

0.211

AC:

32022

AN:

152114

Hom.:

4303

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0578

Gnomad AMI

AF:

0.304

Gnomad AMR

AF:

0.199

Gnomad ASJ

AF:

0.380

Gnomad EAS

AF:

0.0961

Gnomad SAS

AF:

0.147

Gnomad FIN

AF:

0.245

Gnomad MID

AF:

0.320

Gnomad NFE

AF:

0.303

Gnomad OTH

AF:

0.241

GnomAD3 exomes

AF:

0.226

AC:

53166

AN:

235204

Hom.:

7082

AF XY:

0.231

AC XY:

29858

AN XY:

129018

show subpopulations

Gnomad AFR exome

AF:

0.0497

Gnomad AMR exome

AF:

0.140

Gnomad ASJ exome

AF:

0.368

Gnomad EAS exome

AF:

0.0936

Gnomad SAS exome

AF:

0.151

Gnomad FIN exome

AF:

0.246

Gnomad NFE exome

AF:

0.303

Gnomad OTH exome

AF:

0.255

GnomAD4 exome

AF:

0.273

AC:

396544

AN:

1452872

Hom.:

57376

Cov.:

AF XY:

0.270

AC XY:

195144

AN XY:

721832

show subpopulations

Gnomad4 AFR exome

AF:

0.0494

Gnomad4 AMR exome

AF:

0.146

Gnomad4 ASJ exome

AF:

0.370

Gnomad4 EAS exome

AF:

0.0981

Gnomad4 SAS exome

AF:

0.154

Gnomad4 FIN exome

AF:

0.245

Gnomad4 NFE exome

AF:

0.300

Gnomad4 OTH exome

AF:

0.258

GnomAD4 genome

AF:

0.210

AC:

32016

AN:

152232

Hom.:

4302

Cov.:

AF XY:

0.207

AC XY:

15426

AN XY:

74420

show subpopulations

Gnomad4 AFR

AF:

0.0577

Gnomad4 AMR

AF:

0.199

Gnomad4 ASJ

AF:

0.380

Gnomad4 EAS

AF:

0.0955

Gnomad4 SAS

AF:

0.148

Gnomad4 FIN

AF:

0.245

Gnomad4 NFE

AF:

0.303

Gnomad4 OTH

AF:

0.237

Alfa

AF:

0.285

Hom.:

6208

Bravo

AF:

0.203

TwinsUK

AF:

0.297

AC:

1103

ALSPAC

AF:

0.306

AC:

1178

ESP6500AA

AF:

0.0572

AC:

243

ESP6500EA

AF:

0.296

AC:

2513

ExAC

AF:

0.223

AC:

26852

Asia WGS

AF:

0.0940

AC:

328

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 29, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

MAP3K6-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 21, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.64

BayesDel_noAF

Benign

-0.55

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.075

.;T;T

Eigen

Benign

-0.55

Eigen_PC

Benign

-0.61

FATHMM_MKL

Benign

0.032

LIST_S2

Benign

0.75

T;.;T

MetaRNN

Benign

0.0040

T;T;T

MetaSVM

Benign

-0.98

MutationAssessor

Uncertain

2.3

.;M;M

PrimateAI

Benign

0.45

PROVEAN

Uncertain

-2.5

D;D;D

REVEL

Benign

0.039

Sift

Benign

0.10

T;T;T

Sift4G

Benign

0.15

T;T;T

Polyphen

0.0030

B;B;B

Vest4

0.043

MutPred

0.35

.;Gain of ubiquitination at N622 (P = 0.0066);Gain of ubiquitination at N622 (P = 0.0066);

MPC

1.2

ClinPred

0.0038

GERP RS

-0.34

Varity_R

0.13

gMVP

0.41

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

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