NM_005633.4:c.1074+5G>C

Variant names:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

This summary comes from the ClinGen Evidence Repository: 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) LINK:https://erepo.genome.network/evrepo/ui/classification/CA136073/MONDO:0021060/004

Frequency

Genomes: 𝑓 0.0063 ( 5 hom., cov: 32)

Exomes 𝑓: 0.0080 ( 56 hom. )

Consequence

SOS1
NM_005633.4 splice_region, intron

Scores

Splicing: ADA: 0.2881

Clinical Significance

Benign reviewed by expert panel B:20

Conservation

PhyloP100: 3.54

Publications

3 publications found

Variant links:

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]

SOS1 Gene-Disease associations (from GenCC):

Noonan syndrome
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
Noonan syndrome 4
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae)
fibromatosis, gingival, 1
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
hereditary gingival fibromatosis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
cardiofaciocutaneous syndrome
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
Costello syndrome
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

SOS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BA1

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SOS1	NM_005633.4 link	c.1074+5G>C		splice_region_variant, intron_variant	Intron 8 of 22	ENST00000402219.8	NP_005624.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SOS1	ENST00000402219.8 link	c.1074+5G>C		splice_region_variant, intron_variant	Intron 8 of 22	1	NM_005633.4	ENSP00000384675.2

Frequencies

GnomAD3 genomes

AF:

0.00632

AC:

961

AN:

151978

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.00668

AC:

1658

AN:

248288

AF XY:

0.00637

show subpopulations

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 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.:

Cov.:

AF XY:

0.00777

AC XY:

5590

AN XY:

719738

show subpopulations

African (AFR)

AF:

0.00118

AC:

AN:

33118

American (AMR)

AF:

0.00220

AC:

AN:

44558

Ashkenazi Jewish (ASJ)

AF:

0.00496

AC:

129

AN:

26014

East Asian (EAS)

AF:

0.00

AC:

AN:

39514

South Asian (SAS)

AF:

0.000152

AC:

AN:

85604

European-Finnish (FIN)

AF:

0.00714

AC:

381

AN:

53340

Middle Eastern (MID)

AF:

0.00105

AC:

AN:

5732

European-Non Finnish (NFE)

AF:

0.00961

AC:

10543

AN:

1097346

Other (OTH)

AF:

0.00602

AC:

360

AN:

59822

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

530

1059

1589

2118

2648

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

350

700

1050

1400

1750

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00632

AC:

961

AN:

152096

Hom.:

Cov.:

AF XY:

0.00589

AC XY:

438

AN XY:

74336

show subpopulations

African (AFR)

AF:

0.00176

AC:

AN:

41498

American (AMR)

AF:

0.00268

AC:

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.00634

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.000207

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00664

AC:

AN:

10542

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0109

AC:

742

AN:

67986

Other (OTH)

AF:

0.00285

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

104

155

207

259

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00985

Hom.:

Bravo

AF:

0.00563

ClinVar

Significance: Benign

Submissions summary: Benign:20

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Benign:7

Mar 25, 2011

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Jul 01, 2010

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 15, 2015

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

May 22, 2013

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 19, 2011

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:6

Oct 04, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 21, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

SOS1: BP4, BS2 -

RASopathy

Benign:2

Apr 18, 2017

ClinGen RASopathy Variant Curation Expert Panel

Significance:Benign

Review Status:reviewed by expert panel

Collection Method:curation

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) -

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Noonan syndrome 4

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Oct 08, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiovascular phenotype

Benign:1

May 13, 2016

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

May 28, 2021

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.27

CADD

Benign

(source)

DANN

Benign

0.96

PhyloP100

3.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.2

Mutation Taster

=89/11

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over