rs397517167
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Variant summary
Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_StrongBS1BS2
The NM_005633.4(SOS1):c.345+13_345+14insCT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000559 in 1,611,884 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.00048 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00057 ( 2 hom. )
Consequence
SOS1
NM_005633.4 intron
NM_005633.4 intron
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.465
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 -16 ACMG points.
BP6
?
Variant 2-39058659-T-TAG is Benign according to our data. Variant chr2-39058659-T-TAG is described in ClinVar as [Likely_benign]. Clinvar id is 45363.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS1
?
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00048 (73/152142) while in subpopulation NFE AF= 0.000913 (62/67894). AF 95% confidence interval is 0.00073. There are 0 homozygotes in gnomad4. There are 32 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
?
High AC in GnomAd4 at 73 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SOS1 | NM_005633.4 | c.345+13_345+14insCT | intron_variant | ENST00000402219.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SOS1 | ENST00000402219.8 | c.345+13_345+14insCT | intron_variant | 1 | NM_005633.4 | A1 |
Frequencies
GnomAD3 genomes ? AF: 0.000480 AC: 73AN: 152024Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000462 AC: 116AN: 250972Hom.: 0 AF XY: 0.000442 AC XY: 60AN XY: 135690
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GnomAD4 exome AF: 0.000567 AC: 828AN: 1459742Hom.: 2 Cov.: 30 AF XY: 0.000522 AC XY: 379AN XY: 726264
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Sep 18, 2012 | 345+12_345+13dupCT in intron 3 of SOS1: This variant is not expected to be clini cal significant because it is not located in the conserved region of the splicin g consensus sequence. - |
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 09, 2019 | Variant summary: SOS1 c.345+12_345+13dupCT 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. 5/5 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 250972 control chromosomes, predominantly at a frequency of 0.00087 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 29 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 Non-Finnish European origin. To our knowledge, 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. - |
RASopathy Benign:2
Benign, criteria provided, single submitter | clinical testing | GeneDx | Apr 07, 2014 | The variant is found in NOONAN,CARDIOMYOPATHY panel(s). - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 21, 2024 | - - |
Noonan syndrome 4 Benign:1
Benign, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | - | - - |
Fibromatosis, gingival, 1 Benign:1
Benign, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | - | - - |
Computational scores
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Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at