NM_004672.5:c.1866C>A

Variant names:

• chr1-27360975-G-T
• rs35659744
• NM_004672.5:c.1866C>A

Variant summary

Our verdict is Benign. The variant received -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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• 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:3
• Conservation: PhyloP100: 0.183
• Publications: 41 publications found

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 Gene-Disease associations (from GenCC):

• hereditary diffuse gastric adenocarcinoma

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• gastric cancer

  Inheritance: Unknown Classification: LIMITED Submitted by: Laboratory for Molecular Medicine

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004672.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAP3K6	NM_004672.5	MANE Select	c.1866C>A	p.Asn622Lys	missense	Exon 14 of 29	NP_004663.3
	MAP3K6	NM_001297609.2		c.1842C>A	p.Asn614Lys	missense	Exon 13 of 28	NP_001284538.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAP3K6	ENST00000357582.3	TSL:1 MANE Select	c.1866C>A	p.Asn622Lys	missense	Exon 14 of 29	ENSP00000350195.2
	MAP3K6	ENST00000374040.7	TSL:1	c.1842C>A	p.Asn614Lys	missense	Exon 13 of 28	ENSP00000363152.2
	MAP3K6	ENST00000493901.6	TSL:5	n.1470C>A		non_coding_transcript_exon	Exon 12 of 27

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

GnomAD2 exomes AF: 0.226 AC: 53166 AN: 235204 AF XY: 0.231

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 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

African (AFR) AF: 0.0494 AC: 1645 AN: 33318

American (AMR) AF: 0.146 AC: 6458 AN: 44110

Ashkenazi Jewish (ASJ) AF: 0.370 AC: 9564 AN: 25816

East Asian (EAS) AF: 0.0981 AC: 3873 AN: 39484

South Asian (SAS) AF: 0.154 AC: 13111 AN: 85410

European-Finnish (FIN) AF: 0.245 AC: 12698 AN: 51756

Middle Eastern (MID) AF: 0.277 AC: 1585 AN: 5720

European-Non Finnish (NFE) AF: 0.300 AC: 332161 AN: 1107396

Other (OTH) AF: 0.258 AC: 15449 AN: 59862

GnomAD4 genome AF: 0.210 AC: 32016 AN: 152232 Hom.: 4302 Cov.: 33 AF XY: 0.207 AC XY: 15426 AN XY: 74420

African (AFR) AF: 0.0577 AC: 2399 AN: 41576

American (AMR) AF: 0.199 AC: 3038 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.380 AC: 1319 AN: 3470

East Asian (EAS) AF: 0.0955 AC: 493 AN: 5162

South Asian (SAS) AF: 0.148 AC: 714 AN: 4828

European-Finnish (FIN) AF: 0.245 AC: 2591 AN: 10596

Middle Eastern (MID) AF: 0.316 AC: 93 AN: 294

European-Non Finnish (NFE) AF: 0.303 AC: 20591 AN: 67980

Other (OTH) AF: 0.237 AC: 501 AN: 2112

Alfa AF: 0.261 Hom.: 8966

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

Submissions by phenotype

not specified Benign:1

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

MAP3K6-related disorder Benign:1

Oct 21, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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 v4.9

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
DEOGEN2	Benign	0.075	T
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.61
FATHMM_MKL	Benign	0.032	N
LIST_S2	Benign	0.75	T
MetaRNN	Benign	0.0040	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		0.18
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-2.5	D
REVEL	Benign	0.039
Sift	Benign	0.10	T
Sift4G	Benign	0.15	T
Polyphen		0.0030	B
Vest4		0.043
MutPred		0.35		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
Mutation Taster		=98/2	polymorphism (auto)

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

Other links and lift over

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