1-27356039-C-G

Position:

• chr1-27356039-C-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_004672.5(MAP3K6):​c.3698G>C​(p.Gly1233Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0436 in 1,613,976 control chromosomes in the GnomAD database, including 3,011 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.086 (1122 hom., cov: 32)
  • Exomes 𝑓: 0.039 (1889 hom.)
• Consequence: MAP3K6 NM_004672.5 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: -0.0560

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=6.355047E-4).
• BP6: Variant 1-27356039-C-G is Benign according to our data. Variant chr1-27356039-C-G is described in ClinVar as [Benign]. Clinvar id is 3055994.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.215 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MAP3K6	NM_004672.5	c.3698G>C	p.Gly1233Ala	missense_variant	27/29	ENST00000357582.3	NP_004663.3
MAP3K6	NM_001297609.2	c.3674G>C	p.Gly1225Ala	missense_variant	26/28		NP_001284538.1
MAP3K6	XM_047433689.1	c.3605G>C	p.Gly1202Ala	missense_variant	28/30		XP_047289645.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAP3K6	ENST00000357582.3	c.3698G>C	p.Gly1233Ala	missense_variant	27/29	1	NM_004672.5	ENSP00000350195.2

Frequencies

GnomAD3 genomes AF: 0.0858 AC: 13050 AN: 152122 Hom.: 1116 Cov.: 32

Gnomad AFR AF: 0.219

Gnomad AMI AF: 0.128

Gnomad AMR AF: 0.0503

Gnomad ASJ AF: 0.0386

Gnomad EAS AF: 0.000770

Gnomad SAS AF: 0.0354

Gnomad FIN AF: 0.0122

Gnomad MID AF: 0.0665

Gnomad NFE AF: 0.0365

Gnomad OTH AF: 0.0817

GnomAD3 exomes AF: 0.0437 AC: 10987 AN: 251338 Hom.: 566 AF XY: 0.0413 AC XY: 5614 AN XY: 135850

Gnomad AFR exome AF: 0.225

Gnomad AMR exome AF: 0.0332

Gnomad ASJ exome AF: 0.0376

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.0329

Gnomad FIN exome AF: 0.0135

Gnomad NFE exome AF: 0.0373

Gnomad OTH exome AF: 0.0435

GnomAD4 exome AF: 0.0391 AC: 57220 AN: 1461736 Hom.: 1889 Cov.: 32 AF XY: 0.0390 AC XY: 28373 AN XY: 727186

Gnomad4 AFR exome AF: 0.222

Gnomad4 AMR exome AF: 0.0350

Gnomad4 ASJ exome AF: 0.0416

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.0350

Gnomad4 FIN exome AF: 0.0148

Gnomad4 NFE exome AF: 0.0360

Gnomad4 OTH exome AF: 0.0486

GnomAD4 genome AF: 0.0860 AC: 13090 AN: 152240 Hom.: 1122 Cov.: 32 AF XY: 0.0831 AC XY: 6185 AN XY: 74444

Gnomad4 AFR AF: 0.219

Gnomad4 AMR AF: 0.0502

Gnomad4 ASJ AF: 0.0386

Gnomad4 EAS AF: 0.000771

Gnomad4 SAS AF: 0.0361

Gnomad4 FIN AF: 0.0122

Gnomad4 NFE AF: 0.0365

Gnomad4 OTH AF: 0.0814

Alfa AF: 0.0513 Hom.: 138

Bravo AF: 0.0963

TwinsUK AF: 0.0337 AC: 125

ALSPAC AF: 0.0420 AC: 162

ESP6500AA AF: 0.200 AC: 881

ESP6500EA AF: 0.0372 AC: 320

ExAC AF: 0.0465 AC: 5649

Asia WGS AF: 0.0260 AC: 92 AN: 3478

EpiCase AF: 0.0409

EpiControl AF: 0.0451

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

MAP3K6-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 24, 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	0.075
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	12
DANN	Benign	0.79
DEOGEN2	Benign	0.022	.;T;T
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.62
FATHMM_MKL	Benign	0.54	D
LIST_S2	Benign	0.66	T;.;T
MetaRNN	Benign	0.00064	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.2	.;L;L
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.13	N;N;N
REVEL	Benign	0.031
Sift	Benign	0.82	T;T;T
Sift4G	Benign	0.77	T;T;T
Polyphen		0.0	B;B;B
Vest4		0.092
MPC		0.34
ClinPred		0.0085	T
GERP RS		0.77
Varity_R		0.021
gMVP		0.14

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs17162549; hg19: chr1-27682530;