rs8192671

Variant names:

• chr2-38996971-T-C
• rs8192671
• NM_005633.4:c.3032A>G

Your query was ambiguous. Multiple possible variants found:

• chr2-38996971-T-C
• chr2-38996971-T-G

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.3032A>G (p.Asn1011Ser) variant in the SOS1 gene is 0.26% for European (Non-Finnish) chromosomes by the Exome Aggregation Consortium (197/66620 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/CA136129/MONDO:0021060/004

• Frequency:
  • Genomes: 𝑓 0.0016 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0025 (4 hom.)
• Consequence: SOS1 NM_005633.4 missense
• Clinical Significance: Benign reviewed by expert panel B:17
• Conservation: PhyloP100: 5.80
• Publications: 10 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: 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SOS1	NM_005633.4	MANE Select	c.3032A>G	p.Asn1011Ser	missense	Exon 19 of 23	NP_005624.2
	SOS1	NM_001382394.1		c.3011A>G	p.Asn1004Ser	missense	Exon 19 of 23	NP_001369323.1
	SOS1	NM_001382395.1		c.3032A>G	p.Asn1011Ser	missense	Exon 19 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.3032A>G	p.Asn1011Ser	missense	Exon 19 of 23	ENSP00000384675.2	Q07889-1
	SOS1	ENST00000395038.6	TSL:5	c.3032A>G	p.Asn1011Ser	missense	Exon 19 of 22	ENSP00000378479.2	G5E9C8
	SOS1	ENST00000913801.1		c.2912A>G	p.Asn971Ser	missense	Exon 18 of 22	ENSP00000583860.1

Frequencies

GnomAD3 genomes AF: 0.00158 AC: 240 AN: 152200 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000982

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00281

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.00176 AC: 442 AN: 251138 AF XY: 0.00162

Gnomad AFR exome AF: 0.000370

Gnomad AMR exome AF: 0.000694

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000878

Gnomad NFE exome AF: 0.00315

Gnomad OTH exome AF: 0.00294

GnomAD4 exome AF: 0.00246 AC: 3575 AN: 1455044 Hom.: 4 Cov.: 28 AF XY: 0.00243 AC XY: 1761 AN XY: 724382

African (AFR) AF: 0.000360 AC: 12 AN: 33332

American (AMR) AF: 0.000671 AC: 30 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.0000384 AC: 1 AN: 26066

East Asian (EAS) AF: 0.00 AC: 0 AN: 39502

South Asian (SAS) AF: 0.000430 AC: 37 AN: 86098

European-Finnish (FIN) AF: 0.00172 AC: 92 AN: 53392

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5746

European-Non Finnish (NFE) AF: 0.00299 AC: 3302 AN: 1106096

Other (OTH) AF: 0.00166 AC: 100 AN: 60108

GnomAD4 genome AF: 0.00158 AC: 240 AN: 152318 Hom.: 1 Cov.: 32 AF XY: 0.00145 AC XY: 108 AN XY: 74486

African (AFR) AF: 0.000481 AC: 20 AN: 41584

American (AMR) AF: 0.000981 AC: 15 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.000941 AC: 10 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00281 AC: 191 AN: 68008

Other (OTH) AF: 0.00142 AC: 3 AN: 2116

Alfa AF: 0.00238 Hom.: 2

Bravo AF: 0.00142

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.00279 AC: 24

ExAC AF: 0.00189 AC: 230

Asia WGS AF: 0.000289 AC: 1 AN: 3472

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	5	not specified (5)
-	-	2	RASopathy (2)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Fibromatosis, gingival, 1 (1)
-	-	1	Noonan syndrome 4 (1)
-	-	1	Noonan syndrome 4;C4551558:Fibromatosis, gingival, 1 (1)
-	-	1	Noonan syndrome and Noonan-related syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.54	D
Eigen	Benign	-0.065
Eigen_PC	Benign	0.12
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.0053	T
MetaRNN	Benign	0.013	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.60	N
PhyloP100		5.8
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.079
Sift	Benign	0.10	T
Sift4G	Benign	0.27	T
Polyphen		0.0050	B
Vest4		0.37
MVP		0.40
MPC		0.079
ClinPred		0.020	T
GERP RS		5.4
Varity_R		0.29
gMVP		0.43
Mutation Taster		=98/2	polymorphism

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: rs8192671; hg19: chr2-39224112;