rs376722127

Variant names:

• chr2-38995183-A-T
• rs376722127
• NM_005633.4:c.3286T>A

Variant summary

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

This summary comes from the ClinGen Evidence Repository: The c.3286T>A (p.Ser1096Thr) variant in SOS1 has been observed in 0.01864% (24/128738) of non-Finnish European chromosomes in gnomAD v2.1.1. This variant was seen in several individuals whose clinical presentations lacked clear associations with a RASopathy (PMIDs: 22589294, 26580448, 27153395; Invitae internal data, SCV000659145.1; Baylor internal data; Greenwood Genetic Center internal data). Of note, this variant has also been seen in apparently unaffected parental samples (n=14) evaluated during whole exome sequencing suggesting that this variant may be likely benign; however, these cases were not well-phenotyped and therefore do not meet current requirements for BS2 (BS2 not met; GeneDx internal data). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, the clinical significance of this variant is uncertain. LINK:https://erepo.genome.network/evrepo/ui/classification/CA1624230/MONDO:0021060/004

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00039 (0 hom.)
• Consequence: SOS1 NM_005633.4 missense
• Clinical Significance: Uncertain significance reviewed by expert panel U:4 B:5
• Conservation: PhyloP100: 6.56
• Publications: 3 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: Uncertain_significance. The variant received 0 ACMG points.

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.3286T>A	p.Ser1096Thr	missense	Exon 20 of 23	NP_005624.2
	SOS1	NM_001382394.1		c.3265T>A	p.Ser1089Thr	missense	Exon 20 of 23	NP_001369323.1
	SOS1	NM_001382395.1		c.3286T>A	p.Ser1096Thr	missense	Exon 20 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.3286T>A	p.Ser1096Thr	missense	Exon 20 of 23	ENSP00000384675.2	Q07889-1
	SOS1	ENST00000395038.6	TSL:5	c.3286T>A	p.Ser1096Thr	missense	Exon 20 of 22	ENSP00000378479.2	G5E9C8
	SOS1	ENST00000913801.1		c.3166T>A	p.Ser1056Thr	missense	Exon 19 of 22	ENSP00000583860.1

Frequencies

GnomAD3 genomes AF: 0.000164 AC: 25 AN: 152218 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000323

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000996 AC: 25 AN: 250948 AF XY: 0.0000811

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000194

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000385 AC: 563 AN: 1461514 Hom.: 0 Cov.: 31 AF XY: 0.000366 AC XY: 266 AN XY: 727080

African (AFR) AF: 0.0000299 AC: 1 AN: 33464

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.000499 AC: 555 AN: 1111704

Other (OTH) AF: 0.000116 AC: 7 AN: 60376

GnomAD4 genome AF: 0.000164 AC: 25 AN: 152218 Hom.: 0 Cov.: 32 AF XY: 0.000121 AC XY: 9 AN XY: 74366

African (AFR) AF: 0.0000482 AC: 2 AN: 41452

American (AMR) AF: 0.0000654 AC: 1 AN: 15280

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5206

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000323 AC: 22 AN: 68044

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.000225 Hom.: 0

Bravo AF: 0.000166

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000988 AC: 12

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: reviewed by expert panel

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.17
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.53	D
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.047	D
MetaRNN	Benign	0.25	T
MetaSVM	Benign	-0.46	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		6.6
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-0.92	N
REVEL	Uncertain	0.33
Sift	Benign	0.037	D
Sift4G	Benign	0.19	T
Polyphen		0.82	P
Vest4		0.45
MVP		0.71
MPC		0.18
ClinPred		0.070	T
GERP RS		5.9
Varity_R		0.17
gMVP		0.42
Mutation Taster		=78/22	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: rs376722127; hg19: chr2-39222324; COSMIC: COSV67677123; COSMIC: COSV67677123;