rs141565234

Positions:

• chr2-38989315-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 6P and 4B. PVS1_Moderate PP3_Strong BS2

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
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:12 O:1
• 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]

ACMG classification

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: 30 AN: 152080 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.000136 AC: 34 AN: 250150 Hom.: 0 AF XY: 0.000155 AC XY: 21 AN XY: 135222

Gnomad AFR exome AF: 0.0000617

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.000199

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000230

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.000155 AC: 225 AN: 1449826 Hom.: 0 Cov.: 27 AF XY: 0.000168 AC XY: 121 AN XY: 722038

Gnomad4 AFR exome AF: 0.0000301

Gnomad4 AMR exome AF: 0.000247

Gnomad4 ASJ exome AF: 0.0000384

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000177

Gnomad4 OTH exome AF: 0.000284

GnomAD4 genome AF: 0.000197 AC: 30 AN: 152198 Hom.: 0 Cov.: 32 AF XY: 0.000175 AC XY: 13 AN XY: 74402

Gnomad4 AFR AF: 0.0000963

Gnomad4 AMR AF: 0.000393

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000250

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.000185 Hom.: 0

Bravo AF: 0.000238

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000124 AC: 15

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000382

EpiControl AF: 0.000356

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:12 Other:1

Revision: criteria provided, multiple submitters, no conflicts

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:2 Other: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: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.25
CADD	Pathogenic	29
DANN	Uncertain	0.99
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Uncertain	0.85	D
MutationTaster	Benign	1.0	D;D;D
GERP RS		5.2

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.89		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.89		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs141565234; hg19: chr2-39216456; COSMIC: COSV67675033; COSMIC: COSV67675033;