rs702689

chr5-56881616-G-Achr5-56881616-G-C

Variant summary

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

The NM_005921.2(MAP3K1):c.2416G>A(p.Asp806Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.671 in 1,612,860 control chromosomes in the GnomAD database, including 374,698 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.61 (29280 hom., cov: 31)
  • Exomes 𝑓: 0.68 (345418 hom.)
• Consequence: MAP3K1 NM_005921.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 8.19

Genes affected

MAP3K1 (HGNC:6848): (mitogen-activated protein kinase kinase kinase 1) The protein encoded by this gene is a serine/threonine kinase and is part of some signal transduction cascades, including the ERK and JNK kinase pathways as well as the NF-kappa-B pathway. The encoded protein is activated by autophosphorylation and requires magnesium as a cofactor in phosphorylating other proteins. This protein has E3 ligase activity conferred by a plant homeodomain (PHD) in its N-terminus and phospho-kinase activity conferred by a kinase domain in its C-terminus. [provided by RefSeq, Mar 2012]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.4606336E-5).
• BP6: Variant 5-56881616-G-A is Benign according to our data. Variant chr5-56881616-G-A is described in ClinVar as [Benign]. Clinvar id is 518364.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-56881616-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.71 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MAP3K1	NM_005921.2	c.2416G>A	p.Asp806Asn	missense_variant	14/20	ENST00000399503.4
MAP3K1	XM_047417218.1	c.2416G>A	p.Asp806Asn	missense_variant	14/18
MAP3K1	XM_047417219.1	c.2005G>A	p.Asp669Asn	missense_variant	15/21
MAP3K1	XM_047417220.1	c.2005G>A	p.Asp669Asn	missense_variant	15/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAP3K1	ENST00000399503.4	c.2416G>A	p.Asp806Asn	missense_variant	14/20	1	NM_005921.2	P1

Frequencies

GnomAD3 genomes AF: 0.607 AC: 92147 AN: 151850 Hom.: 29262 Cov.: 31

Gnomad AFR AF: 0.489

Gnomad AMI AF: 0.629

Gnomad AMR AF: 0.498

Gnomad ASJ AF: 0.721

Gnomad EAS AF: 0.231

Gnomad SAS AF: 0.481

Gnomad FIN AF: 0.721

Gnomad MID AF: 0.583

Gnomad NFE AF: 0.716

Gnomad OTH AF: 0.628

GnomAD3 exomes AF: 0.594 AC: 147940 AN: 249066 Hom.: 47342 AF XY: 0.603 AC XY: 81451 AN XY: 135130

Gnomad AFR exome AF: 0.490

Gnomad AMR exome AF: 0.415

Gnomad ASJ exome AF: 0.728

Gnomad EAS exome AF: 0.206

Gnomad SAS exome AF: 0.499

Gnomad FIN exome AF: 0.722

Gnomad NFE exome AF: 0.712

Gnomad OTH exome AF: 0.632

GnomAD4 exome AF: 0.678 AC: 990820 AN: 1460892 Hom.: 345418 Cov.: 50 AF XY: 0.674 AC XY: 490099 AN XY: 726832

Gnomad4 AFR exome AF: 0.486

Gnomad4 AMR exome AF: 0.425

Gnomad4 ASJ exome AF: 0.729

Gnomad4 EAS exome AF: 0.236

Gnomad4 SAS exome AF: 0.505

Gnomad4 FIN exome AF: 0.719

Gnomad4 NFE exome AF: 0.722

Gnomad4 OTH exome AF: 0.649

GnomAD4 genome AF: 0.607 AC: 92200 AN: 151968 Hom.: 29280 Cov.: 31 AF XY: 0.600 AC XY: 44550 AN XY: 74300

Gnomad4 AFR AF: 0.490

Gnomad4 AMR AF: 0.498

Gnomad4 ASJ AF: 0.721

Gnomad4 EAS AF: 0.232

Gnomad4 SAS AF: 0.482

Gnomad4 FIN AF: 0.721

Gnomad4 NFE AF: 0.716

Gnomad4 OTH AF: 0.623

Alfa AF: 0.681 Hom.: 91833

Bravo AF: 0.585

TwinsUK AF: 0.724 AC: 2684

ALSPAC AF: 0.722 AC: 2782

ESP6500AA AF: 0.495 AC: 1844

ESP6500EA AF: 0.721 AC: 5908

ExAC AF: 0.598 AC: 72226

Asia WGS AF: 0.379 AC: 1319 AN: 3478

EpiCase AF: 0.711

EpiControl AF: 0.710

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

46,XY sex reversal 6 Benign:3

Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Nov 02, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 12, 2018

This variant is associated with the following publications: (PMID: 22468730, 24497709) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.52
Cadd	Benign	22
Dann	Uncertain	1.0
DEOGEN2	Benign	0.069	T
Eigen	Pathogenic	0.68
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D
MetaRNN	Benign	0.000015	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Uncertain	2.1	M
MutationTaster	Benign	0.000015	P
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-0.10	N
REVEL	Benign	0.15
Sift	Benign	0.20	T
Sift4G	Benign	0.65	T
Polyphen		1.0	D
Vest4		0.33
MPC		0.26
ClinPred		0.044	T
GERP RS		5.6
Varity_R		0.37
gMVP		0.46

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: rs702689; hg19: chr5-56177443; COSMIC: COSV68121807; COSMIC: COSV68121807;