chr5-56881916-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_005921.2(MAP3K1):​c.2716G>A​(p.Val906Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.801 in 1,613,750 control chromosomes in the GnomAD database, including 520,423 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 0.77 ( 45806 hom., cov: 30)
Exomes 𝑓: 0.80 ( 474617 hom. )

Consequence

MAP3K1
NM_005921.2 missense

Scores

1
17

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 1.45
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=7.638531E-7).
BP6
Variant 5-56881916-G-A is Benign according to our data. Variant chr5-56881916-G-A is described in ClinVar as [Benign]. Clinvar id is 518365.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-56881916-G-A is described in Lovd as [Benign].
BA1
GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.815 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
MAP3K1NM_005921.2 linkuse as main transcriptc.2716G>A p.Val906Ile missense_variant 14/20 ENST00000399503.4
MAP3K1XM_047417218.1 linkuse as main transcriptc.2716G>A p.Val906Ile missense_variant 14/18
MAP3K1XM_047417219.1 linkuse as main transcriptc.2305G>A p.Val769Ile missense_variant 15/21
MAP3K1XM_047417220.1 linkuse as main transcriptc.2305G>A p.Val769Ile missense_variant 15/21

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
MAP3K1ENST00000399503.4 linkuse as main transcriptc.2716G>A p.Val906Ile missense_variant 14/201 NM_005921.2 P1

Frequencies

GnomAD3 genomes
AF:
0.773
AC:
117429
AN:
151824
Hom.:
45752
Cov.:
30
show subpopulations
Gnomad AFR
AF:
0.747
Gnomad AMI
AF:
0.712
Gnomad AMR
AF:
0.674
Gnomad ASJ
AF:
0.819
Gnomad EAS
AF:
0.578
Gnomad SAS
AF:
0.769
Gnomad FIN
AF:
0.809
Gnomad MID
AF:
0.706
Gnomad NFE
AF:
0.821
Gnomad OTH
AF:
0.774
GnomAD3 exomes
AF:
0.758
AC:
188624
AN:
248982
Hom.:
72588
AF XY:
0.767
AC XY:
103576
AN XY:
135060
show subpopulations
Gnomad AFR exome
AF:
0.747
Gnomad AMR exome
AF:
0.591
Gnomad ASJ exome
AF:
0.821
Gnomad EAS exome
AF:
0.567
Gnomad SAS exome
AF:
0.775
Gnomad FIN exome
AF:
0.806
Gnomad NFE exome
AF:
0.820
Gnomad OTH exome
AF:
0.771
GnomAD4 exome
AF:
0.803
AC:
1174502
AN:
1461808
Hom.:
474617
Cov.:
60
AF XY:
0.803
AC XY:
583889
AN XY:
727192
show subpopulations
Gnomad4 AFR exome
AF:
0.739
Gnomad4 AMR exome
AF:
0.600
Gnomad4 ASJ exome
AF:
0.825
Gnomad4 EAS exome
AF:
0.569
Gnomad4 SAS exome
AF:
0.778
Gnomad4 FIN exome
AF:
0.807
Gnomad4 NFE exome
AF:
0.824
Gnomad4 OTH exome
AF:
0.788
GnomAD4 genome
AF:
0.774
AC:
117538
AN:
151942
Hom.:
45806
Cov.:
30
AF XY:
0.769
AC XY:
57084
AN XY:
74254
show subpopulations
Gnomad4 AFR
AF:
0.747
Gnomad4 AMR
AF:
0.674
Gnomad4 ASJ
AF:
0.819
Gnomad4 EAS
AF:
0.579
Gnomad4 SAS
AF:
0.769
Gnomad4 FIN
AF:
0.809
Gnomad4 NFE
AF:
0.821
Gnomad4 OTH
AF:
0.776
Alfa
AF:
0.802
Hom.:
125229
Bravo
AF:
0.760
TwinsUK
AF:
0.828
AC:
3072
ALSPAC
AF:
0.826
AC:
3184
ESP6500AA
AF:
0.745
AC:
2819
ESP6500EA
AF:
0.823
AC:
6785
ExAC
AF:
0.764
AC:
92324
Asia WGS
AF:
0.697
AC:
2425
AN:
3478
EpiCase
AF:
0.815
EpiControl
AF:
0.817

ClinVar

Significance: Benign
Submissions summary: Benign:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

46,XY sex reversal 6 Benign:3
Benign, criteria provided, single submitterclinical testingInvitaeJan 31, 2024- -
Benign, no assertion criteria providedclinical testingDiagnostic Laboratory, Department of Genetics, University Medical Center Groningen-- -
Benign, criteria provided, single submitterclinical testingClinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical CenterNov 02, 2017- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.076
BayesDel_addAF
Benign
-0.81
T
BayesDel_noAF
Benign
-0.79
CADD
Benign
8.2
DANN
Benign
0.14
DEOGEN2
Benign
0.076
T
Eigen
Benign
-0.98
Eigen_PC
Benign
-0.90
FATHMM_MKL
Uncertain
0.77
D
LIST_S2
Benign
0.31
T
MetaRNN
Benign
7.6e-7
T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
0.11
N
MutationTaster
Benign
1.0
P
PrimateAI
Benign
0.28
T
PROVEAN
Benign
0.11
N
REVEL
Benign
0.080
Sift
Benign
0.85
T
Sift4G
Benign
0.46
T
Polyphen
0.0
B
Vest4
0.0090
MPC
0.19
ClinPred
0.0037
T
GERP RS
3.6
Varity_R
0.024
gMVP
0.092

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.

Other links and lift over

dbSNP: rs832582; hg19: chr5-56177743; COSMIC: COSV68122270; COSMIC: COSV68122270; API