rs2888586

Variant names:

• chr2-39020148-T-C
• rs2888586
• NM_005633.4:c.1858+2422A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005633.4(SOS1):​c.1858+2422A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.466 in 151,376 control chromosomes in the GnomAD database, including 19,686 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.47 (19686 hom., cov: 31)
• Consequence: SOS1 NM_005633.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.90
• 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: 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.666 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SOS1	NM_005633.4	c.1858+2422A>G		intron_variant	Intron 10 of 22	ENST00000402219.8	NP_005624.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SOS1	ENST00000402219.8	c.1858+2422A>G		intron_variant	Intron 10 of 22	1	NM_005633.4	ENSP00000384675.2

Frequencies

GnomAD3 genomes AF: 0.466 AC: 70470 AN: 151258 Hom.: 19675 Cov.: 31

Gnomad AFR AF: 0.139

Gnomad AMI AF: 0.584

Gnomad AMR AF: 0.577

Gnomad ASJ AF: 0.522

Gnomad EAS AF: 0.685

Gnomad SAS AF: 0.552

Gnomad FIN AF: 0.605

Gnomad MID AF: 0.580

Gnomad NFE AF: 0.590

Gnomad OTH AF: 0.503

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.466 AC: 70487 AN: 151376 Hom.: 19686 Cov.: 31 AF XY: 0.470 AC XY: 34755 AN XY: 73996

African (AFR) AF: 0.138 AC: 5733 AN: 41436

American (AMR) AF: 0.578 AC: 8770 AN: 15182

Ashkenazi Jewish (ASJ) AF: 0.522 AC: 1806 AN: 3460

East Asian (EAS) AF: 0.685 AC: 3531 AN: 5158

South Asian (SAS) AF: 0.553 AC: 2662 AN: 4816

European-Finnish (FIN) AF: 0.605 AC: 6386 AN: 10548

Middle Eastern (MID) AF: 0.575 AC: 168 AN: 292

European-Non Finnish (NFE) AF: 0.590 AC: 39835 AN: 67478

Other (OTH) AF: 0.508 AC: 1065 AN: 2096

Alfa AF: 0.546 Hom.: 14059

Bravo AF: 0.452

Asia WGS AF: 0.598 AC: 2073 AN: 3470

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.28
DANN	Benign	0.55
PhyloP100		-1.9
Mutation Taster		=100/0	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: rs2888586; hg19: chr2-39247289;