2-39054764-G-C

Variant names:

• chr2-39054764-G-C
• rs55980502
• NM_005633.4:c.570C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005633.4(SOS1):​c.570C>G​(p.Asp190Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D190H) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SOS1 NM_005633.4 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 2.03
• Publications: 2 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: 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

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13111556).

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.570C>G	p.Asp190Glu	missense	Exon 5 of 23	NP_005624.2
	SOS1	NM_001382394.1		c.549C>G	p.Asp183Glu	missense	Exon 5 of 23	NP_001369323.1
	SOS1	NM_001382395.1		c.570C>G	p.Asp190Glu	missense	Exon 5 of 22	NP_001369324.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SOS1	ENST00000402219.8	TSL:1 MANE Select	c.570C>G	p.Asp190Glu	missense	Exon 5 of 23	ENSP00000384675.2
	SOS1	ENST00000395038.6	TSL:5	c.570C>G	p.Asp190Glu	missense	Exon 5 of 22	ENSP00000378479.2
	SOS1	ENST00000913801.1		c.570C>G	p.Asp190Glu	missense	Exon 5 of 22	ENSP00000583860.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	1	-	SOS1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Uncertain	0.033	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	17
DANN	Benign	0.61
DEOGEN2	Benign	0.32	T
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.35
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.54	T
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.13	T
MetaSVM	Uncertain	-0.12	T
MutationAssessor	Benign	1.4	L
PhyloP100		2.0
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	0.37	N
REVEL	Uncertain	0.38
Sift	Benign	0.72	T
Sift4G	Benign	1.0	T
Polyphen		0.061	B
Vest4		0.20
MutPred		0.32		Gain of glycosylation at P193 (P = 0.1081)
MVP		0.78
MPC		0.54
ClinPred		0.46	T
GERP RS		5.9
Varity_R		0.062
gMVP		0.21
Mutation Taster		=42/58	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs55980502; hg19: chr2-39281905;