rs150565592

Variant names:

• chr2-39067732-T-C
• rs150565592
• NM_005633.4:c.109A>G

Your query was ambiguous. Multiple possible variants found:

• chr2-39067732-T-C
• chr2-39067732-T-G

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4 BP5 BS4

This summary comes from the ClinGen Evidence Repository: The c.109A>G (p.Thr37Ala) variant did not segregate with disease in affected family members (BS4; Partners LMM internal data; GTR Lab ID: 21766; ClinVar SCV000062187.5). This variant has been identified in a patient with an alternate molecular basis for disease (BP5; Partners LMM internal data; GTR Lab ID: 21766; ClinVar SCV000062187.5). Computational prediction tools and conservation analysis suggest that the p.Thr37Ala variant does not impact the protein (BP4). In summary, this variant meets criteria to be classified as likely benign. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): BS4, BP5, BP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA136074/MONDO:0021060/004

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00027 (0 hom.)
• Consequence: SOS1 NM_005633.4 missense
• Clinical Significance: Likely benign reviewed by expert panel U:1 B:13
• Conservation: PhyloP100: 5.43
• Publications: 13 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: Likely_benign. The variant received -6 ACMG points.

• BP4: For more information check the summary or visit ClinGen Evidence Repository.
• BP5: For more information check the summary or visit ClinGen Evidence Repository.
• BS4: 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.109A>G	p.Thr37Ala	missense	Exon 2 of 23	NP_005624.2
	SOS1	NM_001382394.1		c.88A>G	p.Thr30Ala	missense	Exon 2 of 23	NP_001369323.1
	SOS1	NM_001382395.1		c.109A>G	p.Thr37Ala	missense	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.109A>G	p.Thr37Ala	missense	Exon 2 of 23	ENSP00000384675.2	Q07889-1
	SOS1	ENST00000451331.1	TSL:4	c.-63A>G		5_prime_UTR_premature_start_codon_gain	Exon 2 of 4	ENSP00000393899.1	C9K0N6
	SOS1	ENST00000395038.6	TSL:5	c.109A>G	p.Thr37Ala	missense	Exon 2 of 22	ENSP00000378479.2	G5E9C8

Frequencies

GnomAD3 genomes AF: 0.000145 AC: 22 AN: 152036 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000725

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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: 0.000265

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000131 AC: 33 AN: 251398 AF XY: 0.000140

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000211

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000271 AC: 395 AN: 1458552 Hom.: 0 Cov.: 29 AF XY: 0.000251 AC XY: 182 AN XY: 725812

African (AFR) AF: 0.00 AC: 0 AN: 33420

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26116

East Asian (EAS) AF: 0.00 AC: 0 AN: 39666

South Asian (SAS) AF: 0.000244 AC: 21 AN: 86190

European-Finnish (FIN) AF: 0.0000750 AC: 4 AN: 53360

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.000321 AC: 356 AN: 1109040

Other (OTH) AF: 0.000232 AC: 14 AN: 60282

GnomAD4 genome AF: 0.000145 AC: 22 AN: 152036 Hom.: 0 Cov.: 32 AF XY: 0.0000808 AC XY: 6 AN XY: 74276

African (AFR) AF: 0.0000725 AC: 3 AN: 41404

American (AMR) AF: 0.0000655 AC: 1 AN: 15258

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10598

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

European-Non Finnish (NFE) AF: 0.000265 AC: 18 AN: 67990

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.000255 Hom.: 0

Bravo AF: 0.000113

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000173 AC: 21

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000436

EpiControl AF: 0.000415

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	2	not specified (2)
-	-	2	RASopathy (2)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Fibromatosis, gingival, 1 (1)
-	1	-	Noonan syndrome 4 (1)
-	-	1	Noonan syndrome and Noonan-related syndrome (1)
-	-	1	SOS1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	22
DANN	Benign	0.94
DEOGEN2	Uncertain	0.47	T
Eigen	Benign	-0.16
Eigen_PC	Benign	0.00074
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-0.55	T
MutationAssessor	Benign	0.90	L
PhyloP100		5.4
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.23
Sift	Benign	0.61	T
Sift4G	Benign	0.53	T
Polyphen		0.0	B
Vest4		0.098
MVP		0.69
MPC		0.55
ClinPred		0.064	T
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.17
gMVP		0.26
Mutation Taster		=69/31	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: rs150565592; hg19: chr2-39294873;