rs56219475

Variant names:

• chr2-39013966-G-A
• rs56219475
• NM_005633.4:c.1964C>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.1964C>T (p.Pro655Leu) variant in the SOS1 gene is 1.153% (803/65674) 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/CA136088/MONDO:0021060/004

• Frequency:
  • Genomes: 𝑓 0.0076 (11 hom., cov: 32)
  • Exomes 𝑓: 0.0086 (74 hom.)
• Consequence: SOS1 NM_005633.4 missense
• Clinical Significance: Benign reviewed by expert panel B:20
• Conservation: PhyloP100: 5.44
• Publications: 20 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.1964C>T	p.Pro655Leu	missense	Exon 12 of 23	NP_005624.2
	SOS1	NM_001382394.1		c.1943C>T	p.Pro648Leu	missense	Exon 12 of 23	NP_001369323.1
	SOS1	NM_001382395.1		c.1964C>T	p.Pro655Leu	missense	Exon 12 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.1964C>T	p.Pro655Leu	missense	Exon 12 of 23	ENSP00000384675.2	Q07889-1
	SOS1	ENST00000395038.6	TSL:5	c.1964C>T	p.Pro655Leu	missense	Exon 12 of 22	ENSP00000378479.2	G5E9C8
	SOS1	ENST00000913801.1		c.1964C>T	p.Pro655Leu	missense	Exon 12 of 22	ENSP00000583860.1

Frequencies

GnomAD3 genomes AF: 0.00762 AC: 1158 AN: 151948 Hom.: 11 Cov.: 32

Gnomad AFR AF: 0.00266

Gnomad AMI AF: 0.0921

Gnomad AMR AF: 0.00466

Gnomad ASJ AF: 0.00260

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.0133

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0106

Gnomad OTH AF: 0.00623

GnomAD2 exomes AF: 0.00745 AC: 1861 AN: 249736 AF XY: 0.00756

Gnomad AFR exome AF: 0.00242

Gnomad AMR exome AF: 0.00409

Gnomad ASJ exome AF: 0.00498

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0121

Gnomad NFE exome AF: 0.0116

Gnomad OTH exome AF: 0.00593

GnomAD4 exome AF: 0.00860 AC: 12493 AN: 1452776 Hom.: 74 Cov.: 28 AF XY: 0.00838 AC XY: 6061 AN XY: 723268

African (AFR) AF: 0.00231 AC: 77 AN: 33292

American (AMR) AF: 0.00419 AC: 187 AN: 44646

Ashkenazi Jewish (ASJ) AF: 0.00388 AC: 101 AN: 26024

East Asian (EAS) AF: 0.00 AC: 0 AN: 39562

South Asian (SAS) AF: 0.000813 AC: 70 AN: 86060

European-Finnish (FIN) AF: 0.0118 AC: 621 AN: 52776

Middle Eastern (MID) AF: 0.00244 AC: 14 AN: 5748

European-Non Finnish (NFE) AF: 0.00999 AC: 11032 AN: 1104642

Other (OTH) AF: 0.00651 AC: 391 AN: 60026

GnomAD4 genome AF: 0.00762 AC: 1158 AN: 152066 Hom.: 11 Cov.: 32 AF XY: 0.00767 AC XY: 570 AN XY: 74340

African (AFR) AF: 0.00265 AC: 110 AN: 41496

American (AMR) AF: 0.00465 AC: 71 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.00260 AC: 9 AN: 3464

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

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4816

European-Finnish (FIN) AF: 0.0133 AC: 141 AN: 10576

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0106 AC: 722 AN: 67958

Other (OTH) AF: 0.00617 AC: 13 AN: 2108

Alfa AF: 0.00972 Hom.: 29

Bravo AF: 0.00730

TwinsUK AF: 0.00836 AC: 31

ALSPAC AF: 0.00882 AC: 34

ESP6500AA AF: 0.00204 AC: 9

ESP6500EA AF: 0.00977 AC: 84

ExAC AF: 0.00782 AC: 949

Asia WGS AF: 0.00145 AC: 5 AN: 3474

EpiCase AF: 0.0106

EpiControl AF: 0.0116

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	-	5	not provided (5)
-	-	3	RASopathy (3)
-	-	1	Arrhythmogenic right ventricular cardiomyopathy (1)
-	-	1	Cardiovascular phenotype (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
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.38
CADD	Uncertain	24
DANN	Benign	0.79
DEOGEN2	Benign	0.36	T
Eigen	Benign	-0.026
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.94	D
MetaRNN	Benign	0.0046	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	L
PhyloP100		5.4
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.091
Sift	Benign	0.31	T
Sift4G	Benign	0.47	T
Polyphen		0.066	B
Vest4		0.28
MVP		0.32
MPC		0.59
ClinPred		0.021	T
GERP RS		5.8
Varity_R		0.34
gMVP		0.76
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: rs56219475; hg19: chr2-39241107; COSMIC: COSV107503036;