2-39104952-A-C

Variant names:

• chr2-39104952-A-C
• rs2168043
• NM_005633.4:c.87+15384T>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.87+15384T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.708 in 152,094 control chromosomes in the GnomAD database, including 41,438 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 0.71 (41438 hom., cov: 33)
• Consequence: SOS1 NM_005633.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.557
• Publications: 11 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.0).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.843 is higher than 0.05.

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.87+15384T>G		intron	N/A	NP_005624.2
	SOS1	NM_001382394.1		c.66+19712T>G		intron	N/A	NP_001369323.1
	SOS1	NM_001382395.1		c.87+15384T>G		intron	N/A	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.87+15384T>G		intron	N/A	ENSP00000384675.2	Q07889-1
	SOS1	ENST00000395038.6	TSL:5	c.87+15384T>G		intron	N/A	ENSP00000378479.2	G5E9C8
	SOS1	ENST00000913801.1		c.87+15384T>G		intron	N/A	ENSP00000583860.1

Frequencies

GnomAD3 genomes AF: 0.708 AC: 107606 AN: 151976 Hom.: 41421 Cov.: 33

Gnomad AFR AF: 0.377

Gnomad AMI AF: 0.857

Gnomad AMR AF: 0.788

Gnomad ASJ AF: 0.759

Gnomad EAS AF: 0.784

Gnomad SAS AF: 0.795

Gnomad FIN AF: 0.873

Gnomad MID AF: 0.768

Gnomad NFE AF: 0.848

Gnomad OTH AF: 0.726

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

GnomAD4 genome AF: 0.708 AC: 107653 AN: 152094 Hom.: 41438 Cov.: 33 AF XY: 0.711 AC XY: 52824 AN XY: 74334

African (AFR) AF: 0.377 AC: 15640 AN: 41472

American (AMR) AF: 0.788 AC: 12028 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.759 AC: 2635 AN: 3470

East Asian (EAS) AF: 0.784 AC: 4056 AN: 5176

South Asian (SAS) AF: 0.796 AC: 3835 AN: 4816

European-Finnish (FIN) AF: 0.873 AC: 9240 AN: 10590

Middle Eastern (MID) AF: 0.760 AC: 222 AN: 292

European-Non Finnish (NFE) AF: 0.848 AC: 57678 AN: 67986

Other (OTH) AF: 0.727 AC: 1539 AN: 2116

Alfa AF: 0.795 Hom.: 23084

Bravo AF: 0.686

Asia WGS AF: 0.777 AC: 2702 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	1.6
DANN	Benign	0.54
PhyloP100		-0.56
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: rs2168043; hg19: chr2-39332093;