rs45556841

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_005921.2(MAP3K1):c.2816C>G(p.Ser939Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0206 in 1,544,892 control chromosomes in the GnomAD database, including 402 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.028 ( 35 hom., cov: 31)

Exomes 𝑓: 0.020 ( 367 hom. )

Consequence

MAP3K1
NM_005921.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 2.11

Variant links:

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]

MAP3K1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0024033189).

BP6

Variant 5-56882016-C-G is Benign according to our data. Variant chr5-56882016-C-G is described in ClinVar as [Benign]. Clinvar id is 471692.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-56882016-C-G is described in Lovd as [Benign]. Variant chr5-56882016-C-G is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.028 (2324/83092) while in subpopulation AMR AF= 0.0418 (401/9598). AF 95% confidence interval is 0.0389. There are 35 homozygotes in gnomad4. There are 1062 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High AC in GnomAd4 at 2324 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAP3K1	NM_005921.2 link	c.2816C>G	p.Ser939Cys	missense_variant	Exon 14 of 20	ENST00000399503.4	NP_005912.1	Q13233
MAP3K1	XM_047417218.1 link	c.2816C>G	p.Ser939Cys	missense_variant	Exon 14 of 18		XP_047273174.1
MAP3K1	XM_047417219.1 link	c.2405C>G	p.Ser802Cys	missense_variant	Exon 15 of 21		XP_047273175.1
MAP3K1	XM_047417220.1 link	c.2405C>G	p.Ser802Cys	missense_variant	Exon 15 of 21		XP_047273176.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAP3K1	ENST00000399503.4 link	c.2816C>G	p.Ser939Cys	missense_variant	Exon 14 of 20	1	NM_005921.2	ENSP00000382423.3		Q13233

Frequencies

GnomAD3 genomes

AF:

0.0280

AC:

2326

AN:

83008

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00799

Gnomad AMI

AF:

0.00484

Gnomad AMR

AF:

0.0420

Gnomad ASJ

AF:

0.0866

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0115

Gnomad FIN

AF:

0.00585

Gnomad MID

AF:

0.0327

Gnomad NFE

AF:

0.0406

Gnomad OTH

AF:

0.0421

GnomAD3 exomes

AF:

0.0158

AC:

3907

AN:

247510

Hom.:

AF XY:

0.0160

AC XY:

2150

AN XY:

134448

show subpopulations

Gnomad AFR exome

AF:

0.00404

Gnomad AMR exome

AF:

0.0186

Gnomad ASJ exome

AF:

0.0435

Gnomad EAS exome

AF:

0.000111

Gnomad SAS exome

AF:

0.00511

Gnomad FIN exome

AF:

0.00331

Gnomad NFE exome

AF:

0.0214

Gnomad OTH exome

AF:

0.0225

GnomAD4 exome

AF:

0.0202

AC:

29477

AN:

1461800

Hom.:

367

Cov.:

AF XY:

0.0196

AC XY:

14265

AN XY:

727196

show subpopulations

Gnomad4 AFR exome

AF:

0.00364

Gnomad4 AMR exome

AF:

0.0189

Gnomad4 ASJ exome

AF:

0.0475

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00585

Gnomad4 FIN exome

AF:

0.00386

Gnomad4 NFE exome

AF:

0.0225

Gnomad4 OTH exome

AF:

0.0212

GnomAD4 genome

AF:

0.0280

AC:

2324

AN:

83092

Hom.:

Cov.:

AF XY:

0.0262

AC XY:

1062

AN XY:

40532

show subpopulations

Gnomad4 AFR

AF:

0.00791

Gnomad4 AMR

AF:

0.0418

Gnomad4 ASJ

AF:

0.0866

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.0124

Gnomad4 FIN

AF:

0.00585

Gnomad4 NFE

AF:

0.0406

Gnomad4 OTH

AF:

0.0416

Alfa

AF:

0.0228

Hom.:

Bravo

AF:

0.0165

ESP6500AA

AF:

0.00525

AC:

ESP6500EA

AF:

0.0231

AC:

191

ExAC

AF:

0.0150

AC:

1816

EpiCase

AF:

0.0255

EpiControl

AF:

0.0278

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Jan 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

MAP3K1: BP4, BS1, BS2 -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not specified

Benign:1

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

46,XY sex reversal 6

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.078

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.60

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.076

Eigen

Benign

-0.20

Eigen_PC

Benign

-0.012

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.63

MetaRNN

Benign

0.0024

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

PrimateAI

Benign

0.31

PROVEAN

Benign

-0.13

REVEL

Benign

0.033

Sift

Uncertain

0.0020

Sift4G

Benign

0.11

Polyphen

0.10

Vest4

0.065

MPC

0.23

ClinPred

0.018

GERP RS

3.9

Varity_R

0.13

gMVP

0.12

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