NM_005633.4:c.720+25C>G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_005633.4(SOS1):c.720+25C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.912 in 1,272,808 control chromosomes in the GnomAD database, including 530,808 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.92 ( 65075 hom., cov: 32)

Exomes 𝑓: 0.91 ( 465733 hom. )

Consequence

SOS1
NM_005633.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5O:1

Conservation

PhyloP100: -0.808

Publications

10 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: Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia, 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

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.89).

BP6

Variant 2-39054589-G-C is Benign according to our data. Variant chr2-39054589-G-C is described in ClinVar as Benign. ClinVar VariationId is 180179.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.963 is higher than 0.05.

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.720+25C>G	intron	N/A	NP_005624.2
SOS1	NM_001382394.1		c.699+25C>G	intron	N/A	NP_001369323.1
SOS1	NM_001382395.1		c.720+25C>G	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.720+25C>G	intron	N/A	ENSP00000384675.2	Q07889-1
SOS1	ENST00000395038.6	TSL:5	c.720+25C>G	intron	N/A	ENSP00000378479.2	G5E9C8
SOS1	ENST00000913801.1		c.720+25C>G	intron	N/A	ENSP00000583860.1

Frequencies

GnomAD3 genomes

AF:

0.924

AC:

140519

AN:

152132

Hom.:

65015

Cov.:

show subpopulations

Gnomad AFR

AF:

0.971

Gnomad AMI

AF:

0.906

Gnomad AMR

AF:

0.904

Gnomad ASJ

AF:

0.891

Gnomad EAS

AF:

0.818

Gnomad SAS

AF:

0.826

Gnomad FIN

AF:

0.913

Gnomad MID

AF:

0.899

Gnomad NFE

AF:

0.919

Gnomad OTH

AF:

0.910

GnomAD2 exomes

AF:

0.902

AC:

222952

AN:

247126

AF XY:

0.897

show subpopulations

Gnomad AFR exome

AF:

0.971

Gnomad AMR exome

AF:

0.931

Gnomad ASJ exome

AF:

0.887

Gnomad EAS exome

AF:

0.828

Gnomad FIN exome

AF:

0.906

Gnomad NFE exome

AF:

0.916

Gnomad OTH exome

AF:

0.890

GnomAD4 exome

AF:

0.911

AC:

1020792

AN:

1120560

Hom.:

465733

Cov.:

AF XY:

0.908

AC XY:

520677

AN XY:

573434

show subpopulations

African (AFR)

AF:

0.973

AC:

26151

AN:

26890

American (AMR)

AF:

0.927

AC:

40863

AN:

44086

Ashkenazi Jewish (ASJ)

AF:

0.888

AC:

21283

AN:

23980

East Asian (EAS)

AF:

0.822

AC:

31286

AN:

38042

South Asian (SAS)

AF:

0.839

AC:

65892

AN:

78572

European-Finnish (FIN)

AF:

0.910

AC:

48241

AN:

53020

Middle Eastern (MID)

AF:

0.871

AC:

3243

AN:

3722

European-Non Finnish (NFE)

AF:

0.921

AC:

739752

AN:

803336

Other (OTH)

AF:

0.901

AC:

44081

AN:

48912

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

4366

8731

13097

17462

21828

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

13346

26692

40038

53384

66730

<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:

0.924

AC:

140638

AN:

152248

Hom.:

65075

Cov.:

AF XY:

0.920

AC XY:

68446

AN XY:

74438

show subpopulations

African (AFR)

AF:

0.971

AC:

40345

AN:

41568

American (AMR)

AF:

0.904

AC:

13821

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.891

AC:

3091

AN:

3470

East Asian (EAS)

AF:

0.819

AC:

4234

AN:

5172

South Asian (SAS)

AF:

0.827

AC:

3987

AN:

4820

European-Finnish (FIN)

AF:

0.913

AC:

9675

AN:

10596

Middle Eastern (MID)

AF:

0.895

AC:

263

AN:

294

European-Non Finnish (NFE)

AF:

0.919

AC:

62476

AN:

68016

Other (OTH)

AF:

0.910

AC:

1920

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

556

1112

1667

2223

2779

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

908

1816

2724

3632

4540

<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:

0.917

Hom.:

11292

Bravo

AF:

0.927

Asia WGS

AF:

0.843

AC:

2927

AN:

3468

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Noonan syndrome (1)

Noonan syndrome 4 (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.89

CADD

Benign

0.13

(source)

DANN

Benign

0.44

PhyloP100

-0.81

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism (auto)

(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

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