Genetic Variant NM_005633.4:c.1230G>A (chr2-39023198-C-T) – ACMG Classification: Benign (-11 pts)

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP7BP5BA1BP4

This summary comes from the ClinGen Evidence Repository: The c.1230G>A variant in the SOS1 gene is a synonymous (silent) variant (p.Gln410=) at a nucleotide that is not highly conserved and not predicted by SpliceAI to impact splicing (BP4, BP7). The filtering allele frequency in gnomAD v4.1.0 is 4.078% (2165/59926 alleles, 47 homozygotes) in the Admixed American population and therefore meets BA1. This variant has been identified in patients with an alternate molecular basis for disease (BP5; Partners LMM internal data GTR Lab ID: 21766, ClinVar SCV000062189.6). In summary, this variant meets criteria to be classified as benign for autosomal dominant RASopathies based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy Variant Curation Expert Panel: BA1, BP4, BP5, BP7 (Specification Version 2.1, 09/17/2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA136077/MONDO:0021060/041

Frequency

Genomes: 𝑓 0.0023 ( 5 hom., cov: 32)

Exomes 𝑓: 0.0018 ( 51 hom. )

Consequence

SOS1
NM_005633.4 synonymous

Scores

Clinical Significance

Benign reviewed by expert panel U:1B:12

Conservation

PhyloP100: 0.0360

Publications

6 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

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 -11 ACMG points.

BP4

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

BP5

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

BP7

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	HGVSp	Effect	Exon Rank	Protein	UniProt
SOS1	NM_005633.4	MANE Select	c.1230G>A	p.Gln410Gln	synonymous	Exon 10 of 23	NP_005624.2
SOS1	NM_001382394.1		c.1209G>A	p.Gln403Gln	synonymous	Exon 10 of 23	NP_001369323.1
SOS1	NM_001382395.1		c.1230G>A	p.Gln410Gln	synonymous	Exon 10 of 22	NP_001369324.1	G5E9C8

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SOS1	ENST00000402219.8	TSL:1 MANE Select	c.1230G>A	p.Gln410Gln	synonymous	Exon 10 of 23	ENSP00000384675.2	Q07889-1
SOS1	ENST00000395038.6	TSL:5	c.1230G>A	p.Gln410Gln	synonymous	Exon 10 of 22	ENSP00000378479.2	G5E9C8
SOS1	ENST00000913801.1		c.1230G>A	p.Gln410Gln	synonymous	Exon 10 of 22	ENSP00000583860.1

Frequencies

GnomAD3 genomes

AF:

0.00234

AC:

355

AN:

151974

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000314

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0178

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0112

Gnomad SAS

AF:

0.000622

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.000955

GnomAD2 exomes

AF:

0.00749

AC:

1872

AN:

250082

AF XY:

0.00584

show subpopulations

Gnomad AFR exome

AF:

0.000124

Gnomad AMR exome

AF:

0.0472

Gnomad ASJ exome

AF:

0.000399

Gnomad EAS exome

AF:

0.0109

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000124

Gnomad OTH exome

AF:

0.00329

GnomAD4 exome

AF:

0.00182

AC:

2664

AN:

1460962

Hom.:

Cov.:

AF XY:

0.00161

AC XY:

1173

AN XY:

726784

show subpopulations

African (AFR)

AF:

0.000120

AC:

AN:

33458

American (AMR)

AF:

0.0424

AC:

1892

AN:

44658

Ashkenazi Jewish (ASJ)

AF:

0.000536

AC:

AN:

26102

East Asian (EAS)

AF:

0.0149

AC:

591

AN:

39672

South Asian (SAS)

AF:

0.000267

AC:

AN:

86154

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53256

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.0000549

AC:

AN:

1111544

Other (OTH)

AF:

0.00129

AC:

AN:

60354

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

137

274

410

547

684

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

160

200

<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:

0.00235

AC:

357

AN:

152092

Hom.:

Cov.:

AF XY:

0.00269

AC XY:

200

AN XY:

74386

show subpopulations

African (AFR)

AF:

0.000313

AC:

AN:

41512

American (AMR)

AF:

0.0179

AC:

273

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.0112

AC:

AN:

5178

South Asian (SAS)

AF:

0.000623

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000118

AC:

AN:

67924

Other (OTH)

AF:

0.000945

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

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:

0.00151

Hom.:

Bravo

AF:

0.00434

Asia WGS

AF:

0.00779

AC:

AN:

3478

EpiCase

AF:

0.000164

EpiControl

AF:

0.000178

ClinVar

ClinVar submissions

Significance:Benign

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

not specified (3)

RASopathy (2)

Cardiovascular phenotype (1)

Fibromatosis, gingival, 1 (1)

Noonan syndrome (1)

Noonan syndrome 4 (1)

Noonan syndrome and Noonan-related syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.53

CADD

Benign

4.5

(source)

DANN

Benign

0.43

PhyloP100

0.036

Mutation Taster

=98/2

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