rs141565234
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Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 6P and 4B. PVS1_ModeratePP3_StrongBS2
The NM_005633.4(SOS1):c.3347-1G>A variant causes a splice acceptor change. The variant allele was found at a frequency of 0.000159 in 1,602,024 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.00020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00016 ( 0 hom. )
Consequence
SOS1
NM_005633.4 splice_acceptor
NM_005633.4 splice_acceptor
Scores
4
2
1
Splicing: ADA: 1.000
2
Clinical Significance
Conservation
PhyloP100: 3.79
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]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 2 ACMG points.
PVS1
?
Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.010994502 fraction of the gene. Cryptic splice site detected, with MaxEntScore 4, offset of 1, new splice context is: ttcttgtttcctttcacaAGcaa. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
PP3
?
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
BS2
?
High AC in GnomAd4 at 30 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SOS1 | NM_005633.4 | c.3347-1G>A | splice_acceptor_variant | ENST00000402219.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SOS1 | ENST00000402219.8 | c.3347-1G>A | splice_acceptor_variant | 1 | NM_005633.4 | A1 |
Frequencies
GnomAD3 genomes ? AF: 0.000197 AC: 30AN: 152080Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000136 AC: 34AN: 250150Hom.: 0 AF XY: 0.000155 AC XY: 21AN XY: 135222
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GnomAD4 exome AF: 0.000155 AC: 225AN: 1449826Hom.: 0 Cov.: 27 AF XY: 0.000168 AC XY: 121AN XY: 722038
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GnomAD4 genome ? AF: 0.000197 AC: 30AN: 152198Hom.: 0 Cov.: 32 AF XY: 0.000175 AC XY: 13AN XY: 74402
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:12Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jun 21, 2023 | Reported as a variant of uncertain significance in 2 individuals with Noonan syndrome, one of whom had additional variants in other genes associated with Noonan spectrum disorders (Justino et al., 2014; Hakami et al., 2016); Reported previously as a variant of uncertain significance in a patient with multiple cafe-au-lait macules; however, no segregation information was provided (Castellanos et al., 2020); Reported previously in a patient who was small for gestational age; however, no further clinical or segregation information was provided (Stalman et al., 2018); Observed in a fetus with increased nuchal translucency (Leach et al., 2019); Canonical splice site variant in a gene or region of a gene for which loss of function is not a well-established mechanism of disease; This variant is associated with the following publications: (PMID: 24896146, 26918529, 29868112, 30838730, 29493581, 31573083, 30050098, 29342293, 36110220) - |
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jul 01, 2023 | SOS1: PP3 - |
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Oct 12, 2023 | - - |
Noonan syndrome 4 Uncertain:2Other:1
not provided, no classification provided | literature only | Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP) | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | St. Jude Molecular Pathology, St. Jude Children's Research Hospital | Sep 14, 2023 | The SOS1 c.3347-1G>A intronic change results in a G to A substitution at the -1 position of intron 20 of the SOS1 gene. This variant has a maximum subpopulation frequency of 0.022% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org). This variant has been reported in individuals with clinical features of SOS1-related conditions (PMID: 24896146, 26918529, 29907801). Algorithms that predict the impact of sequence changes on splicing indicate that this change will result in loss of the native acceptor site. While this variant may cause intron retention and result in protein truncation/loss, the disease mechanism for SOS1 is gain-of-function caused by heterozygous missense changes (PMID: 17143282, 17143285). In addition, natural alternative in-frame splicing between exons 20 and 22 and skipping of exon 21 occurs in a different isoform (NM_001382395). Therefore, future studies are required to further elucidate the biological rule of this variant. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance. - |
not specified Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 03, 2023 | Variant summary: SOS1 c.3347-1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes the canonical 3' acceptor site. Three predict the variant creates an alternate 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00014 in 250350 control chromosomes (gnomAD). The observed variant frequency is approximately 4.5 fold of the estimated maximal expected allele frequency for a pathogenic variant in SOS1 causing Noonan Syndrome And Related Conditions phenotype (3e-05), strongly suggesting that the variant is benign. c.3347-1G>A has been reported in the literature in individuals with Noonan syndrome (Justino_2014) as well as non-specific phenotypes such as a IUGR on ultrasound (Hakami_2016), breast cancer (Torrezan_2018) and cafe-au-lait macules (Castellanos_2020). These report(s) do not provide unequivocal conclusions about association of the variant with Noonan Syndrome And Related Conditions. Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Activating (gain of function) mutations in the SOS1 gene, which participates in the RAS-MAPK pathway, have been reported in patients with Noonan syndrome. This splice-site variant is not consistent with the spectrum of SOS1 mutations (exclusively missense changes and small in-frame deletions reported) in patients with Noonan syndrome (Lepri et al, Human Mutation, 2011). Taken together, based on the evidence outlined above, this variant is classified as VUS-possibly benign, until more functional data become available. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Dec 02, 2013 | The 3347-1G>A variant in SOS1 has not been previously reported in individuals wi th clinical features of a Noonan spectrum disorder, but has been identified in 0 .03% (3/8600) of European American chromosomes by the NHLBI Exome Sequencing Pro ject (http://evs.gs.washington.edu/EVS/; dbSNP rs141565234). The 3347-1G>A varia nt occurs in the invariant region (+/- 1,2) of the splice consensus sequence and is expected to cause altered splicing leading to an abnormal or absent protein. However, loss-of-function variants in SOS1 are not thought to be causative of N oonan spectrum disorders. Additional is needed to fully assess the clinical sign ificance of the 3347-1G>A variant. - |
SOS1-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jan 13, 2023 | The SOS1 c.3347-1G>A variant is predicted to disrupt the AG splice acceptor site and interfere with normal splicing. This variant has been reported as a variant of uncertain significance or likely benign in multiple individuals with Noonan syndrome (Justino et al. 2015. PubMed ID: 24896146; Hakami et al. 2016. PubMed ID: 26918529; Table S2 - Leach et al. 2018. PubMed ID: 29907801). This variant is reported in 0.023% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-39216456-C-T), which is likely too common to be a pathogenic variant (Gelb et al. 2018. PubMed ID: 29493581). Nearly all pathogenic variants in SOS1 are missense and the clinical significance of loss-of-function variants are uncertain. Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Noonan syndrome 4;C4551558:Fibromatosis, gingival, 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Apr 05, 2022 | - - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 04, 2023 | The c.3347-1G>A intronic variant results from a G to A substitution one nucleotide upstream from coding exon 21 of the SOS1 gene. This variant has been identified in an individual with Noonan syndrome in conjunction with three additional variants in other RAS-MAPK pathway genes; however, all four alterations were interpreted as variants of unknown significance (Justino A et al. Eur. J. Hum. Genet., 2015 Mar;23:347-53). In addition, this alteration has been detected in association with varying presentations, including a newborn with prenatally diagnosed intrauterine growth restriction (Hakami F et al. Prenat. Diagn., 2016 May;36:418-23), an individual with cafe au lait macules, an individual with breast cancer (Torrezan GT et al. Front Genet, 2018 May;9:161), a prenatal sample with increased nuchal translucency (Leach NT et al. Genet Med. 2019 Feb;21(2):417-425), and in an individual with intellectual disability, coarse and dysmorphic facial features, ADHD, short stature, ophthalmologic involvement, persistent fetal fingertip and toetip pads, and diffuse hyperpigmentary and hypopigmentary changes who carried a truncating mutation in ARID2 (Khazanchi R et al. Am. J. Med. Genet. A, 2019 May;179:808-812). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. However, loss of function of SOS1 has not been established as a mechanism of disease. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
RASopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 19, 2023 | This sequence change affects an acceptor splice site in intron 20 of the SOS1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), however the current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in SOS1 cause disease. This variant is present in population databases (rs141565234, gnomAD 0.02%). Disruption of this splice site has been observed in individual(s) with clinical features of SOS1-related conditions (PMID: 26918529, 29907801, 31573083). ClinVar contains an entry for this variant (Variation ID: 40726). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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. - |
Noonan syndrome and Noonan-related syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | Jul 13, 2020 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
D;D;D
GERP RS
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_AL_spliceai
Position offset: -1
Find out detailed SpliceAI scores and Pangolin per-transcript scores at