chr2-39035207-C-G

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: 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 -8 ACMG points.

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.1074+5G>C	splice_region intron	N/A	NP_005624.2
SOS1	NM_001382394.1		c.1053+5G>C	splice_region intron	N/A	NP_001369323.1
SOS1	NM_001382395.1		c.1074+5G>C	splice_region 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.1074+5G>C	splice_region intron	N/A	ENSP00000384675.2	Q07889-1
SOS1	ENST00000395038.6	TSL:5	c.1074+5G>C	splice_region intron	N/A	ENSP00000378479.2	G5E9C8
SOS1	ENST00000913801.1		c.1074+5G>C	splice_region intron	N/A	ENSP00000583860.1

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

ClinVar submissions

Significance:Benign

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (7)

not provided (6)

RASopathy (2)

Cardiovascular phenotype (1)

Fibromatosis, gingival, 1 (1)

Noonan syndrome 4 (1)

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

Noonan syndrome and Noonan-related syndrome (1)

Computational scores

Source: dbNSFP v4.9

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

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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