rs1553353452
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP5
The NM_005633.4(SOS1):c.2671G>A(p.Glu891Lys) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: not found (cov: 32)
Consequence
SOS1
NM_005633.4 missense, splice_region
NM_005633.4 missense, splice_region
Scores
3
5
11
Splicing: ADA: 0.9579
2
Clinical Significance
Conservation
PhyloP100: 7.79
Genes affected
SOS1 (HGNC:11187): (SOS Ras/Rac guanine nucleotide exchange factor 1) This gene encodes a protein that is a guanine nucleotide exchange factor for RAS proteins, membrane proteins that bind guanine nucleotides and participate in signal transduction pathways. GTP binding activates and GTP hydrolysis inactivates RAS proteins. The product of this gene may regulate RAS proteins by facilitating the exchange of GTP for GDP. Mutations in this gene are associated with gingival fibromatosis 1 and Noonan syndrome type 4. [provided by RefSeq, Jul 2008]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 3 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 2-39007033-C-T is Pathogenic according to our data. Variant chr2-39007033-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 505408.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Likely_pathogenic=2}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SOS1 | NM_005633.4 | c.2671G>A | p.Glu891Lys | missense_variant, splice_region_variant | 16/23 | ENST00000402219.8 | NP_005624.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SOS1 | ENST00000402219.8 | c.2671G>A | p.Glu891Lys | missense_variant, splice_region_variant | 16/23 | 1 | NM_005633.4 | ENSP00000384675.2 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Cov.: 28
GnomAD4 exome
Cov.:
28
GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:2Uncertain:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Noonan syndrome 4 Pathogenic:1Uncertain:1
Likely pathogenic, criteria provided, single submitter | research | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | Mar 25, 2024 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | May 26, 2020 | Based on the classification scheme VCGS_Germline_v0.6.1, this variant is classified as 3A-VUS. Following criteria are met: 0101 - Gain of function is a known mechanism of disease for this gene. 0107 - This gene is known to be associated with autosomal dominant disease. 0200 - Variant is predicted to result in a missense amino acid change from glutamic acid to lysine (exon 16). It is also a non-canonical splice region variant without proven consequence on splicing (no functional evidence available). 0301 - Variant is absent from gnomAD. 0502 - Missense variant with conflicting in silico predictions and high conservation. Abnormal splicing is not predicted by in silico tools. 0600 - Variant is located in an annotated domain or motif that does not have a well established function (RasGEF domain; PDB, NCBI). 0705 - No comparable variants in relevant codon/region have previous evidence for pathogenicity. 0802 - Moderate previous evidence of pathogenicity in unrelated individuals. It has been previously reported likely pathogenic in a patient with Noonan syndrome (ClinVar). 0905 - No published segregation evidence has been identified for this variant. 1007 - No published functional evidence has been identified for this variant. 1205 - Variant is maternally inherited. - |
Noonan syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Nov 17, 2016 | The p.Glu891Lys variant in SOS1 has been identified by our laboratory as a de no vo variant in one individual with clinical features of Noonan syndrome. This var iant was absent from large population studies. Computational prediction tools an d conservation analysis do not provide strong support for or against an impact t o the protein. In summary, although additional studies are required to fully est ablish its clinical significance, the p.Glu891Lys variant is likely pathogenic. - |
RASopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | May 25, 2022 | This variant has not been reported in the literature in individuals affected with SOS1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 891 of the SOS1 protein (p.Glu891Lys). ClinVar contains an entry for this variant (Variation ID: 505408). 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. 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. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Uncertain
T
BayesDel_noAF
Benign
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Benign
T;T;T
Eigen
Benign
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
.;D;D
M_CAP
Benign
T
MetaRNN
Uncertain
D;D;D
MetaSVM
Benign
T
MutationAssessor
Benign
L;L;.
PrimateAI
Pathogenic
D
PROVEAN
Benign
N;N;N
REVEL
Benign
Sift
Benign
T;T;T
Sift4G
Benign
T;T;T
Polyphen
B;B;.
Vest4
MutPred
Gain of MoRF binding (P = 0.0098);Gain of MoRF binding (P = 0.0098);Gain of MoRF binding (P = 0.0098);
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at