NM_005633.4:c.570C>T

Variant names:

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

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.570C>T (p.Asp190=) variant in the SOS1 gene is 0.314% (234/66628) of European 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/CA136171/MONDO:0021060/004

• Frequency:
  • Genomes: 𝑓 0.0023 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0023 (4 hom.)
• Consequence: SOS1 NM_005633.4 synonymous
• Clinical Significance: Benign reviewed by expert panel B:15
• 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: 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.570C>T	p.Asp190Asp	synonymous	Exon 5 of 23	NP_005624.2
	SOS1	NM_001382394.1		c.549C>T	p.Asp183Asp	synonymous	Exon 5 of 23	NP_001369323.1
	SOS1	NM_001382395.1		c.570C>T	p.Asp190Asp	synonymous	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>T	p.Asp190Asp	synonymous	Exon 5 of 23	ENSP00000384675.2
	SOS1	ENST00000395038.6	TSL:5	c.570C>T	p.Asp190Asp	synonymous	Exon 5 of 22	ENSP00000378479.2
	SOS1	ENST00000913801.1		c.570C>T	p.Asp190Asp	synonymous	Exon 5 of 22	ENSP00000583860.1

Frequencies

GnomAD3 genomes AF: 0.00233 AC: 355 AN: 152070 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000507

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00242

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00605

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00322

Gnomad OTH AF: 0.00478

GnomAD2 exomes AF: 0.00239 AC: 601 AN: 250968 AF XY: 0.00247

Gnomad AFR exome AF: 0.000313

Gnomad AMR exome AF: 0.000781

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00633

Gnomad NFE exome AF: 0.00355

Gnomad OTH exome AF: 0.00294

GnomAD4 exome AF: 0.00228 AC: 3263 AN: 1431700 Hom.: 4 Cov.: 27 AF XY: 0.00229 AC XY: 1637 AN XY: 714142

African (AFR) AF: 0.000609 AC: 20 AN: 32836

American (AMR) AF: 0.000985 AC: 44 AN: 44678

Ashkenazi Jewish (ASJ) AF: 0.000308 AC: 8 AN: 25936

East Asian (EAS) AF: 0.000279 AC: 11 AN: 39440

South Asian (SAS) AF: 0.000456 AC: 39 AN: 85586

European-Finnish (FIN) AF: 0.00708 AC: 378 AN: 53390

Middle Eastern (MID) AF: 0.00193 AC: 11 AN: 5710

European-Non Finnish (NFE) AF: 0.00241 AC: 2617 AN: 1084744

Other (OTH) AF: 0.00227 AC: 135 AN: 59380

GnomAD4 genome AF: 0.00233 AC: 355 AN: 152188 Hom.: 0 Cov.: 32 AF XY: 0.00212 AC XY: 158 AN XY: 74422

African (AFR) AF: 0.000506 AC: 21 AN: 41528

American (AMR) AF: 0.00242 AC: 37 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5188

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4828

European-Finnish (FIN) AF: 0.00605 AC: 64 AN: 10576

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00322 AC: 219 AN: 67998

Other (OTH) AF: 0.00473 AC: 10 AN: 2114

Alfa AF: 0.00243 Hom.: 0

Bravo AF: 0.00221

EpiCase AF: 0.00311

EpiControl AF: 0.00486

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	3	not specified (3)
-	-	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
BayesDel_noAF	Benign	-0.48
CADD	Benign	13
DANN	Benign	0.58
PhyloP100		2.0
Mutation Taster		=97/3	polymorphism

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: rs55980502; hg19: chr2-39281905;