2-39012145-G-T

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.2371C>A (p.Leu791Ile) variant in the SOS1 gene is 0.081% for European (Non-Finnish) chromosomes by the Exome Aggregation Consortium (67/66688 with 95% CI), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert panel for autosomal dominant RASopathy variants (BA1). LINK:https://erepo.genome.network/evrepo/ui/classification/CA136098/MONDO:0021060/004

Frequency

Genomes: 𝑓 0.00053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00044 ( 1 hom. )

Consequence

SOS1
NM_005633.4 missense

Scores

Clinical Significance

Benign reviewed by expert panel U:2B:14

Conservation

PhyloP100: 3.30

Publications

9 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.

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	HGVSp	Effect	Exon Rank	Protein
SOS1	NM_005633.4	MANE Select	c.2371C>A	p.Leu791Ile	missense	Exon 14 of 23	NP_005624.2
SOS1	NM_001382394.1		c.2350C>A	p.Leu784Ile	missense	Exon 14 of 23	NP_001369323.1
SOS1	NM_001382395.1		c.2371C>A	p.Leu791Ile	missense	Exon 14 of 22	NP_001369324.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SOS1	ENST00000402219.8	TSL:1 MANE Select	c.2371C>A	p.Leu791Ile	missense	Exon 14 of 23	ENSP00000384675.2
SOS1	ENST00000395038.6	TSL:5	c.2371C>A	p.Leu791Ile	missense	Exon 14 of 22	ENSP00000378479.2
SOS1	ENST00000913801.1		c.2371C>A	p.Leu791Ile	missense	Exon 14 of 22	ENSP00000583860.1

Frequencies

GnomAD3 genomes

AF:

0.000532

AC:

AN:

152148

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000786

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000911

Gnomad OTH

AF:

0.000955

GnomAD2 exomes

AF:

0.000602

AC:

151

AN:

250972

AF XY:

0.000664

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.000752

Gnomad ASJ exome

AF:

0.0000994

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.00102

Gnomad OTH exome

AF:

0.000653

GnomAD4 exome

AF:

0.000440

AC:

642

AN:

1459604

Hom.:

Cov.:

AF XY:

0.000438

AC XY:

318

AN XY:

726266

show subpopulations

African (AFR)

AF:

0.0000599

AC:

AN:

33410

American (AMR)

AF:

0.000671

AC:

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.0000766

AC:

AN:

26108

East Asian (EAS)

AF:

0.00

AC:

AN:

39660

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86222

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53410

Middle Eastern (MID)

AF:

0.000694

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.000522

AC:

579

AN:

1110012

Other (OTH)

AF:

0.000381

AC:

AN:

60306

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

132

165

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome 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

GnomAD4 genome

AF:

0.000532

AC:

AN:

152266

Hom.:

Cov.:

AF XY:

0.000524

AC XY:

AN XY:

74458

show subpopulations

African (AFR)

AF:

0.0000963

AC:

AN:

41552

American (AMR)

AF:

0.000785

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.000207

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10602

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000912

AC:

AN:

68016

Other (OTH)

AF:

0.000945

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.000590

Hom.:

Bravo

AF:

0.000484

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00128

AC:

ExAC

AF:

0.000651

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00125

EpiControl

AF:

0.00166

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (4)

not provided (3)

Noonan syndrome (2)

RASopathy (2)

Cardiovascular phenotype (1)

Fibromatosis, gingival, 1 (1)

Intellectual disability (1)

Noonan syndrome 4 (1)

Noonan syndrome and Noonan-related syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.45

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.38

Eigen

Uncertain

0.32

Eigen_PC

Uncertain

0.44

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.95

M_CAP

Benign

0.0074

MetaRNN

Benign

0.098

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.030

PhyloP100

3.3

PrimateAI

Pathogenic

0.87

PROVEAN

Benign

-1.6

REVEL

Benign

0.15

Sift

Benign

0.19

Sift4G

Benign

0.11

Polyphen

0.57

Vest4

0.28

MVP

0.38

MPC

1.0

ClinPred

0.041

GERP RS

5.9

PromoterAI

-0.020

Neutral

(source)

Varity_R

0.48

gMVP

0.58

Mutation Taster

=66/34

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

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