chr2-39007017-A-G

Position:

• chr2-39007017-A-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BA1 BP5

This summary comes from the ClinGen Evidence Repository: The c.2673+14T>C intronic variant in SOS1 is classified as benign because it has been identified in 0.34596% (lower bound of the 95% CI of 481/128770) of non-Finnish European chromosomes in gnomAD (BA1; https://gnomad.broadinstitute.org). This variant was observed in 1 individual with Noonan syndrome who also carried a pathogenic variant in SHOC2 sufficient to explain their clinical presentation (BP5; SCV000062214.5). ACMG/AMP Criteria applied: BA1, BP5. LINK:https://erepo.genome.network/evrepo/ui/classification/CA136107/MONDO:0021060/004

• Frequency:
  • Genomes: 𝑓 0.0029 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0034 (18 hom.)
• Consequence: SOS1 NM_005633.4 intron
• Clinical Significance: Benign reviewed by expert panel B:14
• Conservation: PhyloP100: 0.178

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 -9 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SOS1	NM_005633.4	c.2673+14T>C		intron_variant		ENST00000402219.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SOS1	ENST00000402219.8	c.2673+14T>C		intron_variant		1	NM_005633.4	A1

Frequencies

GnomAD3 genomes AF: 0.00294 AC: 447 AN: 152198 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.000651

Gnomad AMI AF: 0.0758

Gnomad AMR AF: 0.00255

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00441

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00205 AC: 515 AN: 250818 Hom.: 1 AF XY: 0.00194 AC XY: 263 AN XY: 135550

Gnomad AFR exome AF: 0.000616

Gnomad AMR exome AF: 0.00180

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000370

Gnomad NFE exome AF: 0.00369

Gnomad OTH exome AF: 0.00278

GnomAD4 exome AF: 0.00340 AC: 4857 AN: 1428034 Hom.: 18 Cov.: 26 AF XY: 0.00323 AC XY: 2304 AN XY: 712742

Gnomad4 AFR exome AF: 0.000458

Gnomad4 AMR exome AF: 0.00206

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000760

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000600

Gnomad4 NFE exome AF: 0.00420

Gnomad4 OTH exome AF: 0.00287

GnomAD4 genome AF: 0.00293 AC: 447 AN: 152316 Hom.: 4 Cov.: 32 AF XY: 0.00277 AC XY: 206 AN XY: 74482

Gnomad4 AFR AF: 0.000649

Gnomad4 AMR AF: 0.00255

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000471

Gnomad4 NFE AF: 0.00441

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00265 Hom.: 0

Bravo AF: 0.00289

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:14

Revision: reviewed by expert panel

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 19, 2012	c.2673+14T>C in Intron 16 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 0.4% (25/7020) of European American chromosomes from a b road population by the NHLBI Exome Sequencing Project (http://evs.gs.washington. edu/EVS;). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 11, 2012	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, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 25, 2019	Variant summary: SOS1 c.2673+14T>C 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 0.0021 in 250818 control chromosomes, predominantly at a frequency of 0.0037 within the Non-Finnish European subpopulation in the gnomAD database, including 1 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 123-folds over 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. c.2673+14T>C has been reported in the literature in individuals affected with Noonan Syndrome and Related Conditions (Lepri_2011). However, authors indicate the variant is unrelated to disease. A ClinVar submission (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as benign. -

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 23, 2021	- -

RASopathy Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, reviewed by expert panel	curation	ClinGen RASopathy Variant Curation Expert Panel	Aug 27, 2019	The c.2673+14T>C intronic variant in SOS1 is classified as benign because it has been identified in 0.34596% (lower bound of the 95% CI of 481/128770) of non-Finnish European chromosomes in gnomAD (BA1; https://gnomad.broadinstitute.org). This variant was observed in 1 individual with Noonan syndrome who also carried a pathogenic variant in SHOC2 sufficient to explain their clinical presentation (BP5; SCV000062214.5). ACMG/AMP Criteria applied: BA1, BP5. -

Noonan syndrome 4 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Aug 12, 2021

- -

Hypertrophic cardiomyopathy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego

Apr 01, 2019

- -

Fibromatosis, gingival, 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
CADD	Benign	14
DANN	Benign	0.83
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs183998234; hg19: chr2-39234158;