rs777475313

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_001003787.4(STRADA):​c.535G>T​(p.Val179Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000155 in 1,613,820 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

STRADA
NM_001003787.4 missense

Scores

4
15

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 2.98
Variant links:
Genes affected
STRADA (HGNC:30172): (STE20 related adaptor alpha) The protein encoded by this gene contains a STE20-like kinase domain, but lacks several residues that are critical for catalytic activity, so it is termed a 'pseudokinase'. The protein forms a heterotrimeric complex with serine/threonine kinase 11 (STK11, also known as LKB1) and the scaffolding protein calcium binding protein 39 (CAB39, also known as MO25). The protein activates STK11 leading to the phosphorylation of both proteins and excluding STK11 from the nucleus. The protein is necessary for STK11-induced G1 cell cycle arrest. A mutation in this gene has been shown to result in polyhydramnios, megalencephaly, and symptomatic epilepsy (PMSE) syndrome. Multiple transcript variants encoding different isoforms have been found for this gene. Additional transcript variants have been described but their full-length nature is not known. [provided by RefSeq, Sep 2009]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.38151234).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
STRADANM_001003787.4 linkuse as main transcriptc.535G>T p.Val179Leu missense_variant 8/13 ENST00000336174.12 NP_001003787.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
STRADAENST00000336174.12 linkuse as main transcriptc.535G>T p.Val179Leu missense_variant 8/131 NM_001003787.4 ENSP00000336655 P1Q7RTN6-1

Frequencies

GnomAD3 genomes
AF:
0.0000329
AC:
5
AN:
152160
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000483
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000441
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000159
AC:
4
AN:
251160
Hom.:
0
AF XY:
0.0000147
AC XY:
2
AN XY:
135736
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000353
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000137
AC:
20
AN:
1461660
Hom.:
0
Cov.:
31
AF XY:
0.0000138
AC XY:
10
AN XY:
727136
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000153
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000329
AC:
5
AN:
152160
Hom.:
0
Cov.:
32
AF XY:
0.0000404
AC XY:
3
AN XY:
74338
show subpopulations
Gnomad4 AFR
AF:
0.0000483
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000441
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000302
ExAC
AF:
0.00000824
AC:
1
EpiCase
AF:
0.0000545
EpiControl
AF:
0.0000593

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsJun 06, 2023The c.535G>T (p.V179L) alteration is located in exon 8 (coding exon 7) of the STRADA gene. This alteration results from a G to T substitution at nucleotide position 535, causing the valine (V) at amino acid position 179 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
Polyhydramnios, megalencephaly, and symptomatic epilepsy Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpNov 14, 2023This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 179 of the STRADA protein (p.Val179Leu). This variant is present in population databases (rs777475313, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with STRADA-related conditions. ClinVar contains an entry for this variant (Variation ID: 536754). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.35
BayesDel_addAF
Benign
-0.094
T
BayesDel_noAF
Benign
-0.27
CADD
Pathogenic
32
DANN
Benign
0.82
DEOGEN2
Benign
0.071
.;.;T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Eigen
Benign
0.069
Eigen_PC
Benign
0.16
FATHMM_MKL
Uncertain
0.87
D
LIST_S2
Benign
0.85
D;.;D;.;D;.;D;D;D;D;T;.;D;D;T;D;D;D;T;T;D;D;D;D;D;D;D;T;T
M_CAP
Benign
0.054
D
MetaRNN
Benign
0.38
T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Benign
-0.37
T
MutationAssessor
Benign
1.2
.;.;L;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
MutationTaster
Benign
1.0
D;D;D;D;D;D;D
PrimateAI
Uncertain
0.56
T
PROVEAN
Benign
-2.2
.;.;N;.;.;N;.;.;N;N;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL
Benign
0.12
Sift
Uncertain
0.010
.;.;D;.;.;D;.;.;D;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G
Benign
0.11
.;.;T;T;.;T;.;.;T;T;.;.;.;.;.;.;.;T;T;.;.;.;.;.;T;.;.;.;.
Polyphen
0.75, 0.79, 0.21, 0.12
.;P;P;B;P;.;.;.;.;B;.;.;.;.;.;.;.;.;.;.;.;.;.;.;B;.;.;.;.
Vest4
0.46, 0.44, 0.46, 0.43, 0.38, 0.43, 0.44
MutPred
0.64
.;.;Loss of ubiquitination at K181 (P = 0.2889);.;.;.;.;.;.;.;.;Loss of ubiquitination at K181 (P = 0.2889);.;Loss of ubiquitination at K181 (P = 0.2889);Loss of ubiquitination at K181 (P = 0.2889);Loss of ubiquitination at K181 (P = 0.2889);Loss of ubiquitination at K181 (P = 0.2889);.;.;Loss of ubiquitination at K181 (P = 0.2889);.;Loss of ubiquitination at K181 (P = 0.2889);.;.;.;.;.;.;Loss of ubiquitination at K181 (P = 0.2889);
MVP
0.81
MPC
0.44
ClinPred
0.23
T
GERP RS
4.7
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.16
gMVP
0.55

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: rs777475313; hg19: chr17-61787897; API