rs35659744

chr1-27360975-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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. 12/19 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.183

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]

ACMG classification

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	UniProt
MAP3K6	NM_004672.5	c.1866C>A	p.Asn622Lys	missense_variant	14/29	ENST00000357582.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAP3K6	ENST00000357582.3	c.1866C>A	p.Asn622Lys	missense_variant	14/29	1	NM_004672.5	P4
MAP3K6	ENST00000374040.7	c.1842C>A	p.Asn614Lys	missense_variant	13/28	1		A2
MAP3K6	ENST00000493901.6	n.1470C>A		non_coding_transcript_exon_variant	12/27	5
MAP3K6	ENST00000671291.1	n.700C>A		non_coding_transcript_exon_variant	7/20

Frequencies

GnomAD3 genomes AF: 0.211 AC: 32022 AN: 152114 Hom.: 4303 Cov.: 33

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

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.: 52 AF XY: 0.270 AC XY: 195144 AN XY: 721832

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.: 33 AF XY: 0.207 AC XY: 15426 AN XY: 74420

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:2

Revision: criteria provided, multiple submitters, no conflicts

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 -

MAP3K6-related condition Benign:1

Benign, criteria provided, single submitter

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	T
BayesDel_noAF	Benign	-0.55
Cadd	Benign	13
Dann	Benign	0.97
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.61
FATHMM_MKL	Benign	0.032	N
LIST_S2	Benign	0.75	T;.;T
MetaRNN	Benign	0.0040	T;T;T
MetaSVM	Benign	-0.98	T
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.45	T
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	T
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

Other links and lift over

dbSNP: rs35659744; hg19: chr1-27687466; COSMIC: COSV62887042; COSMIC: COSV62887042;