17-63704390-G-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001003787.4(STRADA):​c.1051C>A​(p.His351Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000031 in 1,612,552 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 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: 31)
Exomes 𝑓: 0.000031 ( 0 hom. )

Consequence

STRADA
NM_001003787.4 missense

Scores

1
18

Clinical Significance

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

Conservation

PhyloP100: 3.59
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 Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.036933094).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
STRADANM_001003787.4 linkc.1051C>A p.His351Asn missense_variant Exon 11 of 13 ENST00000336174.12 NP_001003787.1 Q7RTN6-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
STRADAENST00000336174.12 linkc.1051C>A p.His351Asn missense_variant Exon 11 of 13 1 NM_001003787.4 ENSP00000336655.6 Q7RTN6-1
ENSG00000125695ENST00000580553.1 linkn.*965C>A non_coding_transcript_exon_variant Exon 10 of 12 5 ENSP00000464100.1 J3QR89
ENSG00000125695ENST00000580553.1 linkn.*965C>A 3_prime_UTR_variant Exon 10 of 12 5 ENSP00000464100.1 J3QR89

Frequencies

GnomAD3 genomes
AF:
0.0000329
AC:
5
AN:
152148
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000193
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:
0.0000410
AC:
10
AN:
244110
Hom.:
0
AF XY:
0.0000679
AC XY:
9
AN XY:
132632
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000330
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.0000962
Gnomad NFE exome
AF:
0.0000183
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000308
AC:
45
AN:
1460404
Hom.:
0
Cov.:
43
AF XY:
0.0000262
AC XY:
19
AN XY:
726332
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000101
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.0000567
Gnomad4 NFE exome
AF:
0.0000315
Gnomad4 OTH exome
AF:
0.0000332
GnomAD4 genome
AF:
0.0000329
AC:
5
AN:
152148
Hom.:
0
Cov.:
31
AF XY:
0.0000135
AC XY:
1
AN XY:
74330
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000193
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000441
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000151
ExAC
AF:
0.0000741
AC:
9

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
May 30, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.1051C>A (p.H351N) alteration is located in exon 11 (coding exon 10) of the STRADA gene. This alteration results from a C to A substitution at nucleotide position 1051, causing the histidine (H) at amino acid position 351 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Polyhydramnios, megalencephaly, and symptomatic epilepsy Uncertain:1
Aug 07, 2022
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces histidine, which is basic and polar, with asparagine, which is neutral and polar, at codon 351 of the STRADA protein (p.His351Asn). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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: 1402661). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest 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
Benign
0.062
BayesDel_addAF
Benign
-0.33
T
BayesDel_noAF
Benign
-0.42
CADD
Benign
19
DANN
Benign
0.81
DEOGEN2
Benign
0.047
.;.;T;.;.;.;.;.;.
Eigen
Benign
-0.94
Eigen_PC
Benign
-0.71
FATHMM_MKL
Uncertain
0.87
D
LIST_S2
Benign
0.81
T;.;T;T;.;T;T;T;T
M_CAP
Benign
0.027
D
MetaRNN
Benign
0.037
T;T;T;T;T;T;T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
-0.20
.;.;N;.;.;.;.;.;.
PrimateAI
Benign
0.37
T
PROVEAN
Benign
-0.49
.;.;N;.;N;.;.;N;.
REVEL
Benign
0.079
Sift
Benign
0.60
.;.;T;.;T;.;.;T;.
Sift4G
Benign
0.50
.;.;T;.;T;.;.;T;.
Polyphen
0.0020, 0.0040
.;B;B;B;.;.;.;B;.
Vest4
0.45, 0.45, 0.26
MutPred
0.34
.;.;Loss of helix (P = 0.0626);.;.;.;.;.;Loss of helix (P = 0.0626);
MVP
0.32
MPC
0.61
ClinPred
0.016
T
GERP RS
3.9
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.31
gMVP
0.33

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: rs376896311; hg19: chr17-61781750; API