rs145155424

chr2-39035207-C-G

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_005633.4(SOS1):c.1074+5G>C variant causes a splice donor 5th base, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00785 in 1,597,144 control chromosomes in the GnomAD database, including 61 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.0063 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0080 (56 hom.)
• Consequence: SOS1 NM_005633.4 splice_donor_5th_base, intron
• Scores: Splicing: ADA: 0.2881
• Clinical Significance: Benign reviewed by expert panel B:20
• Conservation: PhyloP100: 3.54

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 Benign. Variant got -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.27).
• BP6: Variant 2-39035207-C-G is Benign according to our data. Variant chr2-39035207-C-G is described in ClinVar as [Benign]. Clinvar id is 45343.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-39035207-C-G is described in Lovd as [Likely_benign]. Variant chr2-39035207-C-G is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00632 (961/152096) while in subpopulation NFE AF= 0.0109 (742/67986). AF 95% confidence interval is 0.0103. There are 5 homozygotes in gnomad4. There are 438 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 961 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SOS1	NM_005633.4	c.1074+5G>C		splice_donor_5th_base_variant, intron_variant		ENST00000402219.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SOS1	ENST00000402219.8	c.1074+5G>C		splice_donor_5th_base_variant, intron_variant		1	NM_005633.4	A1

Frequencies

GnomAD3 genomes AF: 0.00632 AC: 961 AN: 151978 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.00176

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.00269

Gnomad ASJ AF: 0.00634

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00664

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0109

Gnomad OTH AF: 0.00288

GnomAD3 exomes AF: 0.00668 AC: 1658 AN: 248288 Hom.: 8 AF XY: 0.00637 AC XY: 855 AN XY: 134232

Gnomad AFR exome AF: 0.00138

Gnomad AMR exome AF: 0.00210

Gnomad ASJ exome AF: 0.00528

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000199

Gnomad FIN exome AF: 0.00751

Gnomad NFE exome AF: 0.0117

Gnomad OTH exome AF: 0.00495

GnomAD4 exome AF: 0.00801 AC: 11569 AN: 1445048 Hom.: 56 Cov.: 29 AF XY: 0.00777 AC XY: 5590 AN XY: 719738

Gnomad4 AFR exome AF: 0.00118

Gnomad4 AMR exome AF: 0.00220

Gnomad4 ASJ exome AF: 0.00496

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000152

Gnomad4 FIN exome AF: 0.00714

Gnomad4 NFE exome AF: 0.00961

Gnomad4 OTH exome AF: 0.00602

GnomAD4 genome AF: 0.00632 AC: 961 AN: 152096 Hom.: 5 Cov.: 32 AF XY: 0.00589 AC XY: 438 AN XY: 74336

Gnomad4 AFR AF: 0.00176

Gnomad4 AMR AF: 0.00268

Gnomad4 ASJ AF: 0.00634

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00664

Gnomad4 NFE AF: 0.0109

Gnomad4 OTH AF: 0.00285

Alfa AF: 0.00985 Hom.: 2

Bravo AF: 0.00563

ClinVar

Significance: Benign

Submissions summary: Benign:20

Revision: reviewed by expert panel

Submissions by phenotype

not specified Benign:7

Benign, no assertion criteria provided	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Jan 15, 2015	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Jul 01, 2010	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 19, 2011	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	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 25, 2011	1074+5G>C in intron 8 of SOS1: This variant has not been previously reported in the literature. However, this variant has been identified in 12/1154 (1%) of ind ividual's tested by our laboratory, two of whom have a pathogenic variant in PTP N11. In addition, this variant is located in the 5' splice region but does not a ffect the highly conserved +1 and +2 positions. However, positions +3 to +6 are part of the splicing consensus sequence and variants involving these positions s ometimes affect splicing. This type of variant has not been previously reported as pathogenic in SOS1. Therefore, this variant is likely to be benign. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 22, 2013	- -

not provided Benign:6

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	SOS1: BP4, BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 04, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Apr 21, 2016	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

RASopathy Benign:2

Benign, reviewed by expert panel	curation	ClinGen RASopathy Variant Curation Expert Panel	Apr 18, 2017	The filtering allele frequency of the c.1074+5G>C variant in the SOS1 gene is 1.551% (837/50942) of European chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581) -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Noonan syndrome 4 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Noonan syndrome 4;C4551558:Fibromatosis, gingival, 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 08, 2021

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 13, 2016

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. -

Fibromatosis, gingival, 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Noonan syndrome and Noonan-related syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

May 28, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.27
Cadd	Benign	22
Dann	Benign	0.96
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.2

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.29
dbscSNV1_RF	Benign	0.44
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs145155424; hg19: chr2-39262348;