rs963731

Variant names:

• chr2-38989732-T-C
• rs963731
• NM_005633.4:c.3347-418A>G

Your query was ambiguous. Multiple possible variants found:

• chr2-38989732-T-C
• chr2-38989732-T-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.3347-418A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.899 in 152,106 control chromosomes in the GnomAD database, including 61,889 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 0.90 (61889 hom., cov: 33)
• Consequence: SOS1 NM_005633.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.267
• Publications: 14 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=-0.8).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.941 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.3347-418A>G		intron	N/A	NP_005624.2
	SOS1	NM_001382394.1		c.3326-418A>G		intron	N/A	NP_001369323.1
	SOS1	NM_001382395.1		c.3347-2141A>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.3347-418A>G		intron	N/A	ENSP00000384675.2	Q07889-1
	SOS1	ENST00000395038.6	TSL:5	c.3347-2141A>G		intron	N/A	ENSP00000378479.2	G5E9C8
	SOS1	ENST00000913801.1		c.3227-418A>G		intron	N/A	ENSP00000583860.1

Frequencies

GnomAD3 genomes AF: 0.900 AC: 136714 AN: 151988 Hom.: 61852 Cov.: 33

Gnomad AFR AF: 0.806

Gnomad AMI AF: 0.982

Gnomad AMR AF: 0.924

Gnomad ASJ AF: 0.935

Gnomad EAS AF: 0.820

Gnomad SAS AF: 0.837

Gnomad FIN AF: 0.971

Gnomad MID AF: 0.892

Gnomad NFE AF: 0.947

Gnomad OTH AF: 0.898

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

GnomAD4 genome AF: 0.899 AC: 136805 AN: 152106 Hom.: 61889 Cov.: 33 AF XY: 0.898 AC XY: 66778 AN XY: 74382

African (AFR) AF: 0.805 AC: 33433 AN: 41506

American (AMR) AF: 0.925 AC: 14127 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.935 AC: 3246 AN: 3472

East Asian (EAS) AF: 0.820 AC: 4246 AN: 5176

South Asian (SAS) AF: 0.838 AC: 4049 AN: 4830

European-Finnish (FIN) AF: 0.971 AC: 10288 AN: 10590

Middle Eastern (MID) AF: 0.890 AC: 260 AN: 292

European-Non Finnish (NFE) AF: 0.947 AC: 64372 AN: 67948

Other (OTH) AF: 0.898 AC: 1888 AN: 2102

Alfa AF: 0.930 Hom.: 197897

Bravo AF: 0.892

Asia WGS AF: 0.839 AC: 2875 AN: 3426

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	2.4
DANN	Benign	0.86
PhyloP100		-0.27
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: rs963731; hg19: chr2-39216873;