rs150565592
Variant summary
Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_ModerateBP6_Very_StrongBS2
The NM_005633.4(SOS1):c.109A>G(p.Thr37Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000259 in 1,610,588 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★★).
Frequency
Genomes: 𝑓 0.00014 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00027 ( 0 hom. )
Consequence
SOS1
NM_005633.4 missense
NM_005633.4 missense
Scores
3
15
Clinical Significance
Conservation
PhyloP100: 5.43
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]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -14 ACMG points.
BP4
?
Computational evidence support a benign effect (MetaRNN=0.14435309).
BP6
?
Variant 2-39067732-T-C is Benign according to our data. Variant chr2-39067732-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 40641.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-39067732-T-C is described in Lovd as [Likely_benign]. Variant chr2-39067732-T-C is described in Lovd as [Pathogenic].
BS2
?
High AC in GnomAd at 22 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SOS1 | NM_005633.4 | c.109A>G | p.Thr37Ala | missense_variant | 2/23 | ENST00000402219.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SOS1 | ENST00000402219.8 | c.109A>G | p.Thr37Ala | missense_variant | 2/23 | 1 | NM_005633.4 | A1 |
Frequencies
GnomAD3 genomes ? AF: 0.000145 AC: 22AN: 152036Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000131 AC: 33AN: 251398Hom.: 0 AF XY: 0.000140 AC XY: 19AN XY: 135880
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GnomAD4 exome AF: 0.000271 AC: 395AN: 1458552Hom.: 0 Cov.: 29 AF XY: 0.000251 AC XY: 182AN XY: 725812
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ClinVar
Significance: Likely benign
Submissions summary: Uncertain:1Benign:13
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
not provided Benign:5
Likely benign, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Likely benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Jun 15, 2023 | - - |
Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jan 01, 2024 | SOS1: BP4 - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Jan 08, 2019 | This variant is associated with the following publications: (PMID: 23487764, 21387466) - |
not specified Benign:2
Benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Feb 28, 2018 | p.Thr37Ala in exon 2 of SOS1: This variant is not expected to have clinical sig nificance because it has been identified in 0.026% (34/126670) of European chrom osomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute .org; dbSNP rs150565592). It was identified in one individual with clinical feat ures of Noonan syndrome who also carried a pathogenic variant in PTPN11. This va riant was also identified in that individual's unaffected parent. In addition, i n another family, it was identified in only one of two siblings with a clinical diagnosis of Noonan syndrome. ACMG/AMP Criteria applied: BS1, BS2, BP4, BP5. - |
Likely benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Apr 19, 2016 | - - |
RASopathy Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 10, 2024 | - - |
Likely benign, reviewed by expert panel | curation | ClinGen RASopathy Variant Curation Expert Panel | Apr 03, 2017 | The c.109A>G (p.Thr37Ala) variant did not segregate with disease in affected family members (BS4; Partners LMM internal data; GTR Lab ID: 21766; ClinVar SCV000062187.5). This variant has been identified in a patient with an alternate molecular basis for disease (BP5; Partners LMM internal data; GTR Lab ID: 21766; ClinVar SCV000062187.5). Computational prediction tools and conservation analysis suggest that the p.Thr37Ala variant does not impact the protein (BP4). In summary, this variant meets criteria to be classified as likely benign. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): BS4, BP5, BP4. - |
Noonan syndrome 4 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 28, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
SOS1-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Aug 27, 2020 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 05, 2021 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Fibromatosis, gingival, 1 Benign:1
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 28, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. - |
Noonan syndrome and Noonan-related syndrome Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | Jan 01, 2020 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
Cadd
Benign
Dann
Benign
DEOGEN2
Uncertain
T;T;T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
M_CAP
Benign
D
MetaRNN
Benign
T;T;T
MetaSVM
Benign
T
MutationAssessor
Benign
L;L;.
MutationTaster
Benign
D;N;N;N
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N;N
REVEL
Benign
Sift
Benign
T;T;T
Sift4G
Benign
T;T;T
Polyphen
B;B;.
Vest4
MVP
MPC
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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Score
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at