rs189695571
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Variant summary
Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2
The NM_005633.4(SOS1):c.3081+13A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000453 in 1,299,058 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.0021 ( 1 hom., cov: 33)
Exomes 𝑓: 0.00024 ( 1 hom. )
Consequence
SOS1
NM_005633.4 intron
NM_005633.4 intron
Scores
2
Clinical Significance
Conservation
PhyloP100: -1.75
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 -20 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.83).
BP6
?
Variant 2-38996909-T-C is Benign according to our data. Variant chr2-38996909-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 40717.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS1
?
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00207 (315/152282) while in subpopulation AFR AF= 0.00717 (298/41566). AF 95% confidence interval is 0.0065. There are 1 homozygotes in gnomad4. There are 149 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
?
High AC in GnomAd4 at 315 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SOS1 | NM_005633.4 | c.3081+13A>G | intron_variant | ENST00000402219.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SOS1 | ENST00000402219.8 | c.3081+13A>G | intron_variant | 1 | NM_005633.4 | A1 |
Frequencies
GnomAD3 genomes ? AF: 0.00207 AC: 315AN: 152164Hom.: 1 Cov.: 33
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GnomAD3 exomes AF: 0.000462 AC: 116AN: 250996Hom.: 0 AF XY: 0.000383 AC XY: 52AN XY: 135724
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GnomAD4 exome AF: 0.000239 AC: 274AN: 1146776Hom.: 1 Cov.: 17 AF XY: 0.000186 AC XY: 109AN XY: 586766
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:8
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Benign:4
Benign, criteria provided, single submitter | clinical testing | GeneDx | Jan 02, 2013 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | - | - - |
Benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Mar 19, 2012 | c.3081+13A>G in Intron 19 of SOS1: This variant is not expected to have clinical significance because it is not located within the splice consensus sequence and has been identified in 0.7% (27/3738) of African American chromosomes from a br oad population by the NHLBI Exome Sequencing Project (http://evs.gs.washington.e du/EVS;). - |
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 06, 2020 | Variant summary: SOS1 c.3081+13A>G alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00046 in 250996 control chromosomes, predominantly at a frequency of 0.0065 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 217 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 a benign polymorphism found primarily in populations of African or African-American origin. To our knowledge, no occurrence of c.3081+13A>G in individuals affected with Noonan Syndrome and Related Conditions and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as benign. - |
Noonan syndrome 4 Benign:1
Benign, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | - | - - |
Noonan syndrome 4;C4551558:Fibromatosis, gingival, 1 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jul 23, 2021 | - - |
Fibromatosis, gingival, 1 Benign:1
Benign, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | - | - - |
RASopathy Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | - - |
Computational scores
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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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