2-39013454-A-C

Variant names:

• chr2-39013454-A-C
• rs186640807
• NM_005633.4:c.2167+6T>G

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.2167+6T>G variant in the SOS1 gene is 1.442% (169/10278) 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/CA136097/MONDO:0021060/004

• Frequency:
  • Genomes: 𝑓 0.0047 (7 hom., cov: 32)
  • Exomes 𝑓: 0.00046 (4 hom.)
• Consequence: SOS1 NM_005633.4 splice_region, intron
• Scores: Splicing: ADA: 0.00006936
• Clinical Significance: Benign reviewed by expert panel B:11
• Conservation: PhyloP100: 0.827
• Publications: 1 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SOS1	NM_005633.4	MANE Select	c.2167+6T>G		splice_region intron	N/A	NP_005624.2
	SOS1	NM_001382394.1		c.2146+6T>G		splice_region intron	N/A	NP_001369323.1
	SOS1	NM_001382395.1		c.2167+6T>G		splice_region intron	N/A	NP_001369324.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SOS1	ENST00000402219.8	TSL:1 MANE Select	c.2167+6T>G		splice_region intron	N/A	ENSP00000384675.2
	SOS1	ENST00000395038.6	TSL:5	c.2167+6T>G		splice_region intron	N/A	ENSP00000378479.2
	SOS1	ENST00000913801.1		c.2167+6T>G		splice_region intron	N/A	ENSP00000583860.1

Frequencies

GnomAD3 genomes AF: 0.00463 AC: 704 AN: 151984 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.0163

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00151

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: 0.0000147

Gnomad OTH AF: 0.00288

GnomAD2 exomes AF: 0.00115 AC: 287 AN: 250136 AF XY: 0.000792

Gnomad AFR exome AF: 0.0160

Gnomad AMR exome AF: 0.000608

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000354

Gnomad OTH exome AF: 0.000329

GnomAD4 exome AF: 0.000458 AC: 649 AN: 1418488 Hom.: 4 Cov.: 27 AF XY: 0.000404 AC XY: 286 AN XY: 708580

African (AFR) AF: 0.0171 AC: 555 AN: 32544

American (AMR) AF: 0.000740 AC: 33 AN: 44612

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25824

East Asian (EAS) AF: 0.00 AC: 0 AN: 39464

South Asian (SAS) AF: 0.0000117 AC: 1 AN: 85176

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53370

Middle Eastern (MID) AF: 0.000528 AC: 3 AN: 5680

European-Non Finnish (NFE) AF: 0.0000121 AC: 13 AN: 1072924

Other (OTH) AF: 0.000747 AC: 44 AN: 58894

GnomAD4 genome AF: 0.00466 AC: 709 AN: 152102 Hom.: 7 Cov.: 32 AF XY: 0.00448 AC XY: 333 AN XY: 74356

African (AFR) AF: 0.0164 AC: 679 AN: 41522

American (AMR) AF: 0.00151 AC: 23 AN: 15264

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4810

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10590

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67944

Other (OTH) AF: 0.00285 AC: 6 AN: 2106

Alfa AF: 0.00228 Hom.: 3

Bravo AF: 0.00535

Asia WGS AF: 0.000289 AC: 1 AN: 3474

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: reviewed by expert panel

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	10
DANN	Benign	0.59
PhyloP100		0.83
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000069
dbscSNV1_RF	Benign	0.060
SpliceAI score (max)		0.030		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: rs186640807; hg19: chr2-39240595;