NM_006939.4:c.3490-4delT
Variant summary
Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_StrongBS1BS2
The NM_006939.4(SOS2):c.3490-4delT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0012 in 1,174,898 control chromosomes in the GnomAD database, including 13 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Consequence
NM_006939.4 splice_region, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -16 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SOS2 | ENST00000216373.10 | c.3490-4delT | splice_region_variant, intron_variant | Intron 22 of 22 | 1 | NM_006939.4 | ENSP00000216373.5 | |||
SOS2 | ENST00000543680.5 | c.3391-4delT | splice_region_variant, intron_variant | Intron 21 of 21 | 1 | ENSP00000445328.1 |
Frequencies
GnomAD3 genomes AF: 0.000512 AC: 73AN: 142682Hom.: 0 Cov.: 0
GnomAD3 exomes AF: 0.00342 AC: 355AN: 103896Hom.: 2 AF XY: 0.00399 AC XY: 227AN XY: 56850
GnomAD4 exome AF: 0.00129 AC: 1336AN: 1032128Hom.: 13 Cov.: 24 AF XY: 0.00149 AC XY: 745AN XY: 499010
GnomAD4 genome AF: 0.000504 AC: 72AN: 142770Hom.: 0 Cov.: 0 AF XY: 0.000637 AC XY: 44AN XY: 69026
ClinVar
Submissions by phenotype
Noonan syndrome 9 Benign:3
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not specified Benign:1
Variant summary: SOS2 c.3490-4delT alters a 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 0.0034 in 103896 control chromosomes in the gnomAD database, including 2 homozygotes. The observed variant frequency is approximately 1367 fold of the estimated maximal expected allele frequency for a pathogenic variant in SOS2 causing Noonan Syndrome and Related Conditions phenotype (2.5e-06), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.3490-4delT 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. -
not provided Benign:1
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SOS2-related disorder Benign:1
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
This alteration is classified as 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. -
Noonan syndrome and Noonan-related syndrome Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at