rs397517174

Variant names:

• chr2-39054822-A-C
• rs397517174
• NM_005633.4:c.512T>G

Your query was ambiguous. Multiple possible variants found:

• chr2-39054822-A-C
• chr2-39054822-A-G

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PP2 PP3 PM2 PS4_Moderate PS2

This summary comes from the ClinGen Evidence Repository: The c.512T>G (p.Val171Gly) variant has been identified in a patient with clinical features of a RASopathy in a de novo occurance (PS2; Ambry Genetics internal data, GTR ID: 61756, ClinVar SCV000742607.1) This variant has also been identified in two other independent occurrences in patients with clinical features of a RASopathy (PS4_Moderate PMID:26918529, Partners LMM, Invitae internal data; GTR ID: 21766, 500031 ClinVar SCV000062241.5, SCV000553263.2). Of note, a different likely pathogenic missense variant (p.Val171Ala) has been previously identified at this codon of SOS1 (PM5 not met; ClinVar 45373). The p.Val171Gly variant in the SOS1 gene was absent from gnomAD (PM2). Computational prediction tools and conservation analysis suggest that the p.Val171Gly variant may impact the protein (PP3). Of note, the variant occurs at the second nucleotide of exon 5 (in-frame) but no functional evidence has indicated that the variant would cause skipping of the exon. 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, PS4_Moderate, PM2, PP3, PP2. LINK:https://erepo.genome.network/evrepo/ui/classification/CA136165/MONDO:0018997/004

• Frequency: Genomes: not found (cov: 32)
• Consequence: SOS1 NM_005633.4 missense, splice_region
• Scores: Splicing: ADA: 0.9503
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:1
• Conservation: PhyloP100: 8.64
• Publications: 4 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 10 ACMG points.

• PS2: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: 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.512T>G	p.Val171Gly	missense splice_region	Exon 5 of 23	NP_005624.2
	SOS1	NM_001382394.1		c.491T>G	p.Val164Gly	missense splice_region	Exon 5 of 23	NP_001369323.1
	SOS1	NM_001382395.1		c.512T>G	p.Val171Gly	missense splice_region	Exon 5 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.512T>G	p.Val171Gly	missense splice_region	Exon 5 of 23	ENSP00000384675.2	Q07889-1
	SOS1	ENST00000395038.6	TSL:5	c.512T>G	p.Val171Gly	missense splice_region	Exon 5 of 22	ENSP00000378479.2	G5E9C8
	SOS1	ENST00000913801.1		c.512T>G	p.Val171Gly	missense splice_region	Exon 5 of 22	ENSP00000583860.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 17

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	-	-	Inborn genetic diseases (1)
1	-	-	Noonan syndrome 4 (1)
-	1	-	not specified (1)
1	-	-	RASopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.90	D
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.77	T
M_CAP	Uncertain	0.20	D
MetaRNN	Pathogenic	0.80	D
MetaSVM	Uncertain	0.43	D
MutationAssessor	Benign	1.9	L
PhyloP100		8.6
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-5.5	D
REVEL	Pathogenic	0.73
Sift	Uncertain	0.0060	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.73
MutPred		0.39		Loss of stability (P = 0.0052)
MVP		0.97
MPC		1.8
ClinPred		0.99	D
GERP RS		6.1
Varity_R		0.75
gMVP		0.64
Mutation Taster		=2/98	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.95
dbscSNV1_RF	Benign	0.51
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

Other links and lift over

dbSNP: rs397517174; hg19: chr2-39281963; COSMIC: COSV67677736; COSMIC: COSV67677736;