2-39022772-C-G

Variant names:

• chr2-39022772-C-G
• rs267607079
• NM_005633.4:c.1656G>C

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PM1_Strong PP3 PP2 PS2 PM2 PS4 PS3

This summary comes from the ClinGen Evidence Repository: The c.1656G>C (p.Arg552Ser) variant in SOS1 has been reported as a confirmed de novo occurrence in at least 2 patients with clinical features of a RASopathy (PS2_VeryStrong; PMID 17143282). This variant has also been identified in at least 7 independent occurrences in patients with clinical features of a RASopathy (PS4; PMIDs: 26297936, 25862627, 17143282, 21387466, 19020799, 23885229, 22190897, 19352411). This variant was absent from large population studies (PM2; gnomAD, http://gnomad.broadinstitute.org). In vitro functional studies provide some evidence that the p.Arg552Ser variant may impact protein function (PS3; PMID:27304678). This residue has been identified as a hot spot. These variants would have received PM5_Strong but the RAS EP decided that PM1 and PM5 cannot be used simultaneously and therefore this rule has been upgraded with expert judgement (PM1_Strong). Computational prediction tools and conservation analysis suggest that the p.Arg552Ser variant may impact the protein (PP3). The variant is located in the SOS1 gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID:29493581). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied (PMID:29493581): PS2_VeryStrong, PS4, PM2, PS3, PM1_Strong, PP2, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA256580/MONDO:0021060/004

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SOS1 NM_005633.4 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:14
• Conservation: PhyloP100: 0.623
• Publications: 23 publications found

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

ACMG classification

Our verdict: Pathogenic. The variant received 20 ACMG points.

• PS2: For more information check the summary or visit ClinGen Evidence Repository.
• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP2: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SOS1	NM_005633.4	MANE Select	c.1656G>C	p.Arg552Ser	missense	Exon 10 of 23	NP_005624.2
	SOS1	NM_001382394.1		c.1635G>C	p.Arg545Ser	missense	Exon 10 of 23	NP_001369323.1
	SOS1	NM_001382395.1		c.1656G>C	p.Arg552Ser	missense	Exon 10 of 22	NP_001369324.1	G5E9C8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SOS1	ENST00000402219.8	TSL:1 MANE Select	c.1656G>C	p.Arg552Ser	missense	Exon 10 of 23	ENSP00000384675.2	Q07889-1
	SOS1	ENST00000395038.6	TSL:5	c.1656G>C	p.Arg552Ser	missense	Exon 10 of 22	ENSP00000378479.2	G5E9C8
	SOS1	ENST00000913801.1		c.1656G>C	p.Arg552Ser	missense	Exon 10 of 22	ENSP00000583860.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461482 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727056

African (AFR) AF: 0.00 AC: 0 AN: 33462

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39678

South Asian (SAS) AF: 0.00 AC: 0 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53382

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111718

Other (OTH) AF: 0.00 AC: 0 AN: 60386

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
3	-	-	RASopathy (3)
2	-	-	Noonan syndrome (2)
2	-	-	Noonan syndrome 1 (2)
2	-	-	Noonan syndrome 4 (2)
2	-	-	Noonan syndrome 4;C4551558:Fibromatosis, gingival, 1 (2)
2	-	-	not provided (2)
1	-	-	Noonan syndrome and Noonan-related syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.94	D
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Benign	0.65	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.57	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Uncertain	0.50	D
MutationAssessor	Uncertain	2.6	M
PhyloP100		0.62
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-5.8	D
REVEL	Pathogenic	0.86
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.99
MutPred		0.85		Loss of MoRF binding (P = 0.0526)
MVP		0.99
MPC		1.6
ClinPred		0.99	D
GERP RS		3.0
Varity_R		0.95
gMVP		0.87
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs267607079; hg19: chr2-39249913; COSMIC: COSV67675640; COSMIC: COSV67675640;