2-39006551-G-C

Variant names:

• chr2-39006551-G-C
• rs61601281
• NM_005633.4:c.2674-22C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005633.4(SOS1):​c.2674-22C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00818 in 1,200,238 control chromosomes in the GnomAD database, including 554 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.037 (340 hom., cov: 32)
  • Exomes 𝑓: 0.0040 (214 hom.)
• Consequence: SOS1 NM_005633.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.970
• Publications: 4 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 2-39006551-G-C is Benign according to our data. Variant chr2-39006551-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 259845.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.124 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SOS1	NM_005633.4	MANE Select	c.2674-22C>G		intron	N/A	NP_005624.2
	SOS1	NM_001382394.1		c.2653-22C>G		intron	N/A	NP_001369323.1
	SOS1	NM_001382395.1		c.2674-22C>G		intron	N/A	NP_001369324.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SOS1	ENST00000402219.8	TSL:1 MANE Select	c.2674-22C>G		intron	N/A	ENSP00000384675.2
	SOS1	ENST00000395038.6	TSL:5	c.2674-22C>G		intron	N/A	ENSP00000378479.2
	SOS1	ENST00000692089.1		c.2563-22C>G		intron	N/A	ENSP00000508626.1

Frequencies

GnomAD3 genomes AF: 0.0370 AC: 5619 AN: 151946 Hom.: 337 Cov.: 32

Gnomad AFR AF: 0.126

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0186

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0159

Gnomad NFE AF: 0.000647

Gnomad OTH AF: 0.0273

GnomAD2 exomes AF: 0.00932 AC: 2317 AN: 248512 AF XY: 0.00672

Gnomad AFR exome AF: 0.128

Gnomad AMR exome AF: 0.00652

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000390

Gnomad OTH exome AF: 0.00480

GnomAD4 exome AF: 0.00399 AC: 4177 AN: 1048174 Hom.: 214 Cov.: 15 AF XY: 0.00334 AC XY: 1805 AN XY: 540594

African (AFR) AF: 0.126 AC: 3158 AN: 25106

American (AMR) AF: 0.00722 AC: 318 AN: 44056

Ashkenazi Jewish (ASJ) AF: 0.0000426 AC: 1 AN: 23500

East Asian (EAS) AF: 0.00 AC: 0 AN: 37768

South Asian (SAS) AF: 0.000464 AC: 36 AN: 77540

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52506

Middle Eastern (MID) AF: 0.00818 AC: 40 AN: 4892

European-Non Finnish (NFE) AF: 0.000259 AC: 191 AN: 736200

Other (OTH) AF: 0.00929 AC: 433 AN: 46606

GnomAD4 genome AF: 0.0371 AC: 5638 AN: 152064 Hom.: 340 Cov.: 32 AF XY: 0.0363 AC XY: 2697 AN XY: 74348

African (AFR) AF: 0.127 AC: 5246 AN: 41456

American (AMR) AF: 0.0186 AC: 284 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10570

Middle Eastern (MID) AF: 0.0171 AC: 5 AN: 292

European-Non Finnish (NFE) AF: 0.000647 AC: 44 AN: 67972

Other (OTH) AF: 0.0270 AC: 57 AN: 2112

Alfa AF: 0.00229 Hom.: 4

Bravo AF: 0.0431

Asia WGS AF: 0.00868 AC: 31 AN: 3470

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Jun 26, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Noonan syndrome 4 Benign:1

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Fibromatosis, gingival, 1 Benign:1

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.24
DANN	Benign	0.50
PhyloP100		-0.97
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs61601281; hg19: chr2-39233692;