NM_005633.4:c.195A>C

Variant names:

• chr2-39067646-T-G
• rs7609455
• NM_005633.4:c.195A>C

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.195A>C (p.Arg65=) variant in the SOS1 gene is 10.978% (1192/10346) of African chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581) LINK:https://erepo.genome.network/evrepo/ui/classification/CA136085/MONDO:0021060/004

• Frequency:
  • Genomes: 𝑓 0.036 (303 hom., cov: 32)
  • Exomes 𝑓: 0.0053 (325 hom.)
• Consequence: SOS1 NM_005633.4 synonymous
• Clinical Significance: Benign reviewed by expert panel B:17
• Conservation: PhyloP100: 0.782
• Publications: 12 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

Specifications for SOS1 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

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.195A>C	p.Arg65Arg	synonymous	Exon 2 of 23	NP_005624.2
	SOS1	NM_001382394.1		c.174A>C	p.Arg58Arg	synonymous	Exon 2 of 23	NP_001369323.1
	SOS1	NM_001382395.1		c.195A>C	p.Arg65Arg	synonymous	Exon 2 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.195A>C	p.Arg65Arg	synonymous	Exon 2 of 23	ENSP00000384675.2	Q07889-1
	SOS1	ENST00000395038.6	TSL:5	c.195A>C	p.Arg65Arg	synonymous	Exon 2 of 22	ENSP00000378479.2	G5E9C8
	SOS1	ENST00000913801.1		c.195A>C	p.Arg65Arg	synonymous	Exon 2 of 22	ENSP00000583860.1

Frequencies

GnomAD3 genomes AF: 0.0358 AC: 5448 AN: 152118 Hom.: 299 Cov.: 32

Gnomad AFR AF: 0.116

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0246

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.0229

Gnomad SAS AF: 0.00662

Gnomad FIN AF: 0.000753

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.000926

Gnomad OTH AF: 0.0273

GnomAD2 exomes AF: 0.0122 AC: 3058 AN: 251384 AF XY: 0.00976

Gnomad AFR exome AF: 0.118

Gnomad AMR exome AF: 0.0119

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0178

Gnomad FIN exome AF: 0.00115

Gnomad NFE exome AF: 0.000783

Gnomad OTH exome AF: 0.00783

GnomAD4 exome AF: 0.00534 AC: 7801 AN: 1461164 Hom.: 325 Cov.: 29 AF XY: 0.00501 AC XY: 3640 AN XY: 726882

African (AFR) AF: 0.120 AC: 4017 AN: 33400

American (AMR) AF: 0.0129 AC: 576 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0000766 AC: 2 AN: 26126

East Asian (EAS) AF: 0.0334 AC: 1324 AN: 39672

South Asian (SAS) AF: 0.00742 AC: 640 AN: 86246

European-Finnish (FIN) AF: 0.00120 AC: 64 AN: 53400

Middle Eastern (MID) AF: 0.00780 AC: 45 AN: 5766

European-Non Finnish (NFE) AF: 0.000416 AC: 462 AN: 1111464

Other (OTH) AF: 0.0111 AC: 671 AN: 60368

GnomAD4 genome AF: 0.0359 AC: 5465 AN: 152236 Hom.: 303 Cov.: 32 AF XY: 0.0357 AC XY: 2655 AN XY: 74452

African (AFR) AF: 0.116 AC: 4806 AN: 41500

American (AMR) AF: 0.0246 AC: 376 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.0229 AC: 119 AN: 5186

South Asian (SAS) AF: 0.00621 AC: 30 AN: 4830

European-Finnish (FIN) AF: 0.000753 AC: 8 AN: 10618

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.000926 AC: 63 AN: 68030

Other (OTH) AF: 0.0270 AC: 57 AN: 2110

Alfa AF: 0.0130 Hom.: 135

Bravo AF: 0.0409

Asia WGS AF: 0.0250 AC: 86 AN: 3478

EpiCase AF: 0.000382

EpiControl AF: 0.000593

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	3	not provided (3)
-	-	3	RASopathy (3)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Fibromatosis, gingival, 1 (1)
-	-	1	Noonan syndrome 4 (1)
-	-	1	Noonan syndrome and Noonan-related syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	9.3
DANN	Benign	0.75
PhyloP100		0.78
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=94/6	polymorphism (auto)

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: rs7609455; hg19: chr2-39294787; COSMIC: COSV67674420;