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rs2229883

chr5-56875262-G-Achr5-56875262-G-C

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_StrongBP6_ModerateBP7BS1BS2

The NM_005921.2(MAP3K1):c.1917G>A(p.Leu639=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00172 in 1,614,132 control chromosomes in the GnomAD database, including 31 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0073 ( 21 hom., cov: 32)
Exomes 𝑓: 0.0011 ( 10 hom. )

Consequence

MAP3K1
NM_005921.2 synonymous

Scores

2

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.401
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 -15 ACMG points.

BP4
?
    BP4 - Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
Computational evidence support a benign effect (BayesDel_noAF=-0.52).
BP6
?
    BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 5-56875262-G-A is Benign according to our data. Variant chr5-56875262-G-A is described in ClinVar as [Benign]. Clinvar id is 539065.Status of the report is criteria_provided_single_submitter, 1 stars.
BP7
?
    BP7 - A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved
Synonymous conserved (PhyloP=0.401 with no splicing effect.
BS1
?
    BS1 - Allele frequency is greater than expected for disorder
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00733 (1116/152292) while in subpopulation AFR AF= 0.0242 (1005/41548). AF 95% confidence interval is 0.0229. There are 21 homozygotes in gnomad4. There are 525 alleles in male gnomad4 subpopulation. This position pass quality control queck.
BS2
?
    BS2 - Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age
High AC in GnomAd at 1114 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
MAP3K1NM_005921.2 linkuse as main transcriptc.1917G>A p.Leu639= synonymous_variant 10/20 ENST00000399503.4
MAP3K1XM_047417218.1 linkuse as main transcriptc.1917G>A p.Leu639= synonymous_variant 10/18
MAP3K1XM_047417219.1 linkuse as main transcriptc.1506G>A p.Leu502= synonymous_variant 11/21
MAP3K1XM_047417220.1 linkuse as main transcriptc.1506G>A p.Leu502= synonymous_variant 11/21

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
MAP3K1ENST00000399503.4 linkuse as main transcriptc.1917G>A p.Leu639= synonymous_variant 10/201 NM_005921.2 P1

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.00732
AC:
1114
AN:
152174
Hom.:
21
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0242
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00432
Gnomad ASJ
AF:
0.00375
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.0000943
Gnomad MID
AF:
0.00316
Gnomad NFE
AF:
0.000206
Gnomad OTH
AF:
0.00717
GnomAD3 exomes
AF:
0.00237
AC:
591
AN:
249292
Hom.:
9
AF XY:
0.00171
AC XY:
231
AN XY:
135218
show subpopulations
Gnomad AFR exome
AF:
0.0285
Gnomad AMR exome
AF:
0.00180
Gnomad ASJ exome
AF:
0.00457
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.0000928
Gnomad NFE exome
AF:
0.000283
Gnomad OTH exome
AF:
0.00116
GnomAD4 exome
AF:
0.00113
AC:
1653
AN:
1461840
Hom.:
10
Cov.:
32
AF XY:
0.000991
AC XY:
721
AN XY:
727220
show subpopulations
Gnomad4 AFR exome
AF:
0.0265
Gnomad4 AMR exome
AF:
0.00195
Gnomad4 ASJ exome
AF:
0.00348
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000580
Gnomad4 FIN exome
AF:
0.0000749
Gnomad4 NFE exome
AF:
0.000382
Gnomad4 OTH exome
AF:
0.00237
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.00733
AC:
1116
AN:
152292
Hom.:
21
Cov.:
32
AF XY:
0.00705
AC XY:
525
AN XY:
74478
show subpopulations
Gnomad4 AFR
AF:
0.0242
Gnomad4 AMR
AF:
0.00432
Gnomad4 ASJ
AF:
0.00375
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.0000943
Gnomad4 NFE
AF:
0.000206
Gnomad4 OTH
AF:
0.00710
Alfa
AF:
0.00340
Hom.:
5
Bravo
AF:
0.00841
Asia WGS
AF:
0.00115
AC:
4
AN:
3478
EpiCase
AF:
0.000491
EpiControl
AF:
0.000237

ClinVar

Significance: Benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

46,XY sex reversal 6 Benign:1
Benign, criteria provided, single submitterclinical testingInvitaeDec 11, 2023- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.52
Cadd
Benign
4.3
Dann
Benign
0.68

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs2229883; hg19: chr5-56171089; COSMIC: COSV68126649; API