rs183998234

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BA1BP5

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

Scores

Clinical Significance

Benign reviewed by expert panel B:14

Conservation

PhyloP100: 0.178

Publications

0 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: PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp
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
Noonan syndrome with multiple lentigines
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
Noonan syndrome-like disorder with loose anagen hair
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

SOS1 links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_005633.4, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Specifications for SOS1 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP5

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

BA1

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005633.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
SOS1	NM_005633.4	MANE Select	c.2673+14T>C	intron	N/A	NP_005624.2
SOS1	NM_001382394.1		c.2652+14T>C	intron	N/A	NP_001369323.1
SOS1	NM_001382395.1		c.2673+14T>C	intron	N/A	NP_001369324.1	G5E9C8

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
SOS1	ENST00000402219.8	TSL:1 MANE Select	c.2673+14T>C	intron	N/A	ENSP00000384675.2	Q07889-1
SOS1	ENST00000395038.6	TSL:5	c.2673+14T>C	intron	N/A	ENSP00000378479.2	G5E9C8
SOS1	ENST00000913801.1		c.2553+14T>C	intron	N/A	ENSP00000583860.1

Frequencies

GnomAD3 genomes

AF:

0.00294

AC:

447

AN:

152198

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.00205

AC:

515

AN:

250818

AF XY:

0.00194

show subpopulations

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 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.:

Cov.:

AF XY:

0.00323

AC XY:

2304

AN XY:

712742

show subpopulations

African (AFR)

AF:

0.000458

AC:

AN:

32742

American (AMR)

AF:

0.00206

AC:

AN:

44652

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25918

East Asian (EAS)

AF:

0.0000760

AC:

AN:

39458

South Asian (SAS)

AF:

0.00

AC:

AN:

85194

European-Finnish (FIN)

AF:

0.000600

AC:

AN:

53352

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5704

European-Non Finnish (NFE)

AF:

0.00420

AC:

4545

AN:

1081812

Other (OTH)

AF:

0.00287

AC:

170

AN:

59202

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

219

438

656

875

1094

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

172

344

516

688

860

<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:

0.00293

AC:

447

AN:

152316

Hom.:

Cov.:

AF XY:

0.00277

AC XY:

206

AN XY:

74482

show subpopulations

African (AFR)

AF:

0.000649

AC:

AN:

41586

American (AMR)

AF:

0.00255

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.000471

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00441

AC:

300

AN:

68018

Other (OTH)

AF:

0.00284

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

117

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.00279

Hom.:

Bravo

AF:

0.00289

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (5)

not provided (3)

RASopathy (2)

Fibromatosis, gingival, 1 (1)

Hypertrophic cardiomyopathy (1)

Noonan syndrome 4 (1)

Noonan syndrome 4;C4551558:Fibromatosis, gingival, 1 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.66

CADD

Benign

(source)

DANN

Benign

0.83

PhyloP100

0.18

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism

(source)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over