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GeneBe

6-136592478-G-A

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_StrongBP6_ModerateBP7BS2

The NM_005923.4(MAP3K5):c.3015C>T(p.Cys1005=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00131 in 1,613,878 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.00084 ( 1 hom., cov: 32)
Exomes 𝑓: 0.0014 ( 14 hom. )

Consequence

MAP3K5
NM_005923.4 synonymous

Scores

2

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.146
Variant links:
Genes affected
MAP3K5 (HGNC:6857): (mitogen-activated protein kinase kinase kinase 5) Mitogen-activated protein kinase (MAPK) signaling cascades include MAPK or extracellular signal-regulated kinase (ERK), MAPK kinase (MKK or MEK), and MAPK kinase kinase (MAPKKK or MEKK). MAPKK kinase/MEKK phosphorylates and activates its downstream protein kinase, MAPK kinase/MEK, which in turn activates MAPK. The kinases of these signaling cascades are highly conserved, and homologs exist in yeast, Drosophila, and mammalian cells. MAPKKK5 contains 1,374 amino acids with all 11 kinase subdomains. Northern blot analysis shows that MAPKKK5 transcript is abundantly expressed in human heart and pancreas. The MAPKKK5 protein phosphorylates and activates MKK4 (aliases SERK1, MAPKK4) in vitro, and activates c-Jun N-terminal kinase (JNK)/stress-activated protein kinase (SAPK) during transient expression in COS and 293 cells; MAPKKK5 does not activate MAPK/ERK. [provided by RefSeq, Jul 2008]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -11 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=-0.54).
BP6
?
    BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 6-136592478-G-A is Benign according to our data. Variant chr6-136592478-G-A is described in ClinVar as [Benign]. Clinvar id is 734375.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=-0.146 with no splicing effect.
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 130 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
MAP3K5NM_005923.4 linkuse as main transcriptc.3015C>T p.Cys1005= synonymous_variant 22/30 ENST00000359015.5

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
MAP3K5ENST00000359015.5 linkuse as main transcriptc.3015C>T p.Cys1005= synonymous_variant 22/301 NM_005923.4 P1Q99683-1
MAP3K5ENST00000698928.1 linkuse as main transcriptc.3342C>T p.Cys1114= synonymous_variant 23/31

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.000856
AC:
130
AN:
151892
Hom.:
1
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000218
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000393
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00789
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00112
Gnomad OTH
AF:
0.000479
GnomAD3 exomes
AF:
0.00174
AC:
438
AN:
251376
Hom.:
5
AF XY:
0.00212
AC XY:
288
AN XY:
135862
show subpopulations
Gnomad AFR exome
AF:
0.000308
Gnomad AMR exome
AF:
0.000347
Gnomad ASJ exome
AF:
0.0000993
Gnomad EAS exome
AF:
0.0000544
Gnomad SAS exome
AF:
0.00921
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00112
Gnomad OTH exome
AF:
0.00163
GnomAD4 exome
AF:
0.00136
AC:
1985
AN:
1461868
Hom.:
14
Cov.:
32
AF XY:
0.00158
AC XY:
1148
AN XY:
727236
show subpopulations
Gnomad4 AFR exome
AF:
0.000508
Gnomad4 AMR exome
AF:
0.000537
Gnomad4 ASJ exome
AF:
0.0000765
Gnomad4 EAS exome
AF:
0.000302
Gnomad4 SAS exome
AF:
0.00865
Gnomad4 FIN exome
AF:
0.0000374
Gnomad4 NFE exome
AF:
0.000967
Gnomad4 OTH exome
AF:
0.00159
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.000842
AC:
128
AN:
152010
Hom.:
1
Cov.:
32
AF XY:
0.000861
AC XY:
64
AN XY:
74290
show subpopulations
Gnomad4 AFR
AF:
0.000217
Gnomad4 AMR
AF:
0.000393
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00769
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00110
Gnomad4 OTH
AF:
0.000474
Alfa
AF:
0.000793
Hom.:
0
Bravo
AF:
0.000665
Asia WGS
AF:
0.00346
AC:
12
AN:
3478
EpiCase
AF:
0.00142
EpiControl
AF:
0.00202

ClinVar

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

Submissions by phenotype

not provided Benign:1
Benign, criteria provided, single submitterclinical testingInvitaeJul 26, 2018- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.54
Cadd
Benign
0.32
Dann
Benign
0.59

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: rs150394997; hg19: chr6-136913616; COSMIC: COSV100752529; API