rs3832123

Variant names:

• chr2-38983578-T-TTA
• rs3832123
• NM_005633.4:c.*2244_*2245dupTA

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_005633.4(SOS1):​c.*2244_*2245dupTA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely benign (★★). The gene SOS1 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.80 (50972 hom., cov: 0)
  • Exomes 𝑓: 0.25 (0 hom.)
• Consequence: SOS1 NM_005633.4 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.633
• Publications: 5 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: PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P, 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

Specifications for SOS1 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Benign. The variant received -16 ACMG points.

• BP6: Variant 2-38983578-T-TTA is Benign according to our data. Variant chr2-38983578-T-TTA is described in ClinVar as Likely_benign. ClinVar VariationId is 212289.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.917 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.*2244_*2245dupTA		3_prime_UTR	Exon 23 of 23	NP_005624.2
	SOS1	NM_001382394.1		c.*2244_*2245dupTA		3_prime_UTR	Exon 23 of 23	NP_001369323.1
	SOS1	NM_001382395.1		c.*2244_*2245dupTA		3_prime_UTR	Exon 22 of 22	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.*2244_*2245dupTA		3_prime_UTR	Exon 23 of 23	ENSP00000384675.2	Q07889-1
	SOS1	ENST00000913800.1		c.*2244_*2245dupTA		3_prime_UTR	Exon 21 of 21	ENSP00000583859.1
	SOS1	ENST00000685279.1		c.*2244_*2245dupTA		3_prime_UTR	Exon 15 of 15	ENSP00000509424.1	A0A8I5KY52

Frequencies

GnomAD3 genomes AF: 0.797 AC: 121089 AN: 151862 Hom.: 50955 Cov.: 0

Gnomad AFR AF: 0.500

Gnomad AMI AF: 0.906

Gnomad AMR AF: 0.879

Gnomad ASJ AF: 0.879

Gnomad EAS AF: 0.809

Gnomad SAS AF: 0.826

Gnomad FIN AF: 0.968

Gnomad MID AF: 0.855

Gnomad NFE AF: 0.923

Gnomad OTH AF: 0.822

GnomAD4 exome AF: 0.250 AC: 1 AN: 4 Hom.: 0 Cov.: 0 AF XY: 0.250 AC XY: 1 AN XY: 4

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.250 AC: 1 AN: 4

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.797 AC: 121140 AN: 151980 Hom.: 50972 Cov.: 0 AF XY: 0.799 AC XY: 59366 AN XY: 74292

African (AFR) AF: 0.500 AC: 20689 AN: 41402

American (AMR) AF: 0.880 AC: 13418 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.879 AC: 3046 AN: 3466

East Asian (EAS) AF: 0.809 AC: 4179 AN: 5166

South Asian (SAS) AF: 0.828 AC: 3989 AN: 4820

European-Finnish (FIN) AF: 0.968 AC: 10267 AN: 10610

Middle Eastern (MID) AF: 0.854 AC: 246 AN: 288

European-Non Finnish (NFE) AF: 0.923 AC: 62746 AN: 67956

Other (OTH) AF: 0.823 AC: 1734 AN: 2108

Alfa AF: 0.851 Hom.: 6956

Bravo AF: 0.774

Asia WGS AF: 0.809 AC: 2814 AN: 3476

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Fibromatosis, gingival, 1 (1)
-	-	1	Gingival fibromatosis (1)
-	-	1	Noonan syndrome (1)
-	-	1	Noonan syndrome 4 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.63
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs3832123;

hg19: chr2-39210719;

COSMIC: COSV67673481;

COSMIC: COSV67673481;