rs763337946
Variant summary
Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_StrongBP6_Very_StrongBP7BS2
The NM_005633.4(SOS1):c.39A>G(p.Glu13=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000187 in 1,601,674 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★★).
Frequency
Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000019 ( 0 hom. )
Consequence
SOS1
NM_005633.4 synonymous
NM_005633.4 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -0.237
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 -17 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.64).
BP6
?
Variant 2-39120384-T-C is Benign according to our data. Variant chr2-39120384-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 282591.Status of the report is reviewed_by_expert_panel, 3 stars.
BP7
?
Synonymous conserved (PhyloP=-0.237 with no splicing effect.
BS2
?
High AC in GnomAdExome at 5 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SOS1 | NM_005633.4 | c.39A>G | p.Glu13= | synonymous_variant | 1/23 | ENST00000402219.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SOS1 | ENST00000402219.8 | c.39A>G | p.Glu13= | synonymous_variant | 1/23 | 1 | NM_005633.4 | A1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152104Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000214 AC: 5AN: 233162Hom.: 0 AF XY: 0.0000234 AC XY: 3AN XY: 128000
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GnomAD4 exome AF: 0.0000186 AC: 27AN: 1449570Hom.: 0 Cov.: 31 AF XY: 0.0000125 AC XY: 9AN XY: 721172
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ClinVar
Significance: Likely benign
Submissions summary: Uncertain:2Benign:4
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
not provided Uncertain:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Nov 01, 2022 | SOS1: BP4, BP7 - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Aug 21, 2015 | - - |
RASopathy Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Nov 10, 2022 | - - |
Likely benign, reviewed by expert panel | curation | ClinGen RASopathy Variant Curation Expert Panel | Nov 04, 2019 | The c.39A>G (p.Glu13Glu) variant in SOS1 is classified as likely benign because it does not alter an amino acid residue, is not located within the splice consensus site, and computational splice prediction tools do not predict an impact on splicing (BP4, BP7). It has been identified in 0.004165% (5/120058) of non-Finnish European chromosomes in gnomAD (BS1 not met; https://gnomad.broadinstitute.org). This variant was observed in several individuals with varying clinical presentations that lacked clear associations with a RASopathy. In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied: BP4, BP7. - |
Noonan syndrome and Noonan-related syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | Aug 01, 2018 | - - |
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 07, 2019 | 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. - |
Computational scores
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Name
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BayesDel_noAF
Benign
Cadd
Benign
Dann
Benign
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at