rs145364368

Variant names:

• chr2-38997006-A-G
• rs145364368
• NM_005633.4:c.2997T>C

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

This summary comes from the ClinGen Evidence Repository: The filtering allele frequency of the c.2997T>C (p.Asn999=) variant in the SOS1 gene is 1.009% (120/10162) of African chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581) LINK:https://erepo.genome.network/evrepo/ui/classification/CA136126/MONDO:0021060/004

• Frequency:
  • Genomes: 𝑓 0.0036 (6 hom., cov: 33)
  • Exomes 𝑓: 0.00089 (12 hom.)
• Consequence: SOS1 NM_005633.4 synonymous
• Clinical Significance: Benign reviewed by expert panel B:10
• Conservation: PhyloP100: 0.880
• 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: 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 -8 ACMG points.

• BA1: 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SOS1	NM_005633.4	MANE Select	c.2997T>C	p.Asn999Asn	synonymous	Exon 19 of 23	NP_005624.2
	SOS1	NM_001382394.1		c.2976T>C	p.Asn992Asn	synonymous	Exon 19 of 23	NP_001369323.1
	SOS1	NM_001382395.1		c.2997T>C	p.Asn999Asn	synonymous	Exon 19 of 22	NP_001369324.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SOS1	ENST00000402219.8	TSL:1 MANE Select	c.2997T>C	p.Asn999Asn	synonymous	Exon 19 of 23	ENSP00000384675.2
	SOS1	ENST00000395038.6	TSL:5	c.2997T>C	p.Asn999Asn	synonymous	Exon 19 of 22	ENSP00000378479.2
	SOS1	ENST00000692089.1		c.2886T>C	p.Asn962Asn	synonymous	Exon 18 of 22	ENSP00000508626.1

Frequencies

GnomAD3 genomes AF: 0.00362 AC: 551 AN: 152158 Hom.: 6 Cov.: 33

Gnomad AFR AF: 0.0117

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000523

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0106

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.00212 AC: 531 AN: 250588 AF XY: 0.00221

Gnomad AFR exome AF: 0.0115

Gnomad AMR exome AF: 0.000724

Gnomad ASJ exome AF: 0.0000994

Gnomad EAS exome AF: 0.0000546

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000265

Gnomad OTH exome AF: 0.000493

GnomAD4 exome AF: 0.000886 AC: 1285 AN: 1450824 Hom.: 12 Cov.: 27 AF XY: 0.00113 AC XY: 818 AN XY: 722394

African (AFR) AF: 0.00848 AC: 282 AN: 33274

American (AMR) AF: 0.000783 AC: 35 AN: 44682

Ashkenazi Jewish (ASJ) AF: 0.0000384 AC: 1 AN: 26040

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39452

South Asian (SAS) AF: 0.00997 AC: 855 AN: 85788

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53308

Middle Eastern (MID) AF: 0.000874 AC: 5 AN: 5722

European-Non Finnish (NFE) AF: 0.0000136 AC: 15 AN: 1102552

Other (OTH) AF: 0.00152 AC: 91 AN: 60006

GnomAD4 genome AF: 0.00361 AC: 550 AN: 152276 Hom.: 6 Cov.: 33 AF XY: 0.00369 AC XY: 275 AN XY: 74472

African (AFR) AF: 0.0116 AC: 484 AN: 41550

American (AMR) AF: 0.000523 AC: 8 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5184

South Asian (SAS) AF: 0.0106 AC: 51 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68008

Other (OTH) AF: 0.00142 AC: 3 AN: 2114

Alfa AF: 0.00148 Hom.: 1

Bravo AF: 0.00378

Asia WGS AF: 0.0130 AC: 45 AN: 3474

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	not provided (2)
-	-	2	RASopathy (2)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Noonan syndrome 4;C4551558:Fibromatosis, gingival, 1 (1)
-	-	1	Noonan syndrome and Noonan-related syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	4.2
DANN	Benign	0.51
PhyloP100		0.88
Mutation Taster		=100/0	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: rs145364368; hg19: chr2-39224147;