rs143962515

chr2-39054781-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_005633.4(SOS1):c.553A>G(p.Ile185Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000174 in 1,557,822 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I185T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00018 (2 hom.)
• Consequence: SOS1 NM_005633.4 missense
• Clinical Significance: Benign reviewed by expert panel U:3 B:9
• Conservation: PhyloP100: 0.433

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0050168037).
• BP6: Variant 2-39054781-T-C is Benign according to our data. Variant chr2-39054781-T-C is described in ClinVar as [Benign]. Clinvar id is 45374.Status of the report is reviewed_by_expert_panel, 3 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.000179 (252/1405494) while in subpopulation AMR AF= 0.000941 (42/44638). AF 95% confidence interval is 0.000715. There are 2 homozygotes in gnomad4_exome. There are 132 alleles in male gnomad4_exome subpopulation. Median coverage is 26. This position pass quality control queck.
• BS2: High AC in GnomAd at 19 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SOS1	NM_005633.4	c.553A>G	p.Ile185Val	missense_variant	5/23	ENST00000402219.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SOS1	ENST00000402219.8	c.553A>G	p.Ile185Val	missense_variant	5/23	1	NM_005633.4	A1

Frequencies

GnomAD3 genomes AF: 0.000125 AC: 19 AN: 152210 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000383 AC: 96 AN: 250584 Hom.: 0 AF XY: 0.000398 AC XY: 54 AN XY: 135774

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000925

Gnomad ASJ exome AF: 0.00477

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000881

Gnomad OTH exome AF: 0.000821

GnomAD4 exome AF: 0.000179 AC: 252 AN: 1405494 Hom.: 2 Cov.: 26 AF XY: 0.000188 AC XY: 132 AN XY: 702630

Gnomad4 AFR exome AF: 0.0000618

Gnomad4 AMR exome AF: 0.000941

Gnomad4 ASJ exome AF: 0.00454

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000353

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000509

Gnomad4 OTH exome AF: 0.000512

GnomAD4 genome AF: 0.000125 AC: 19 AN: 152328 Hom.: 0 Cov.: 32 AF XY: 0.0000671 AC XY: 5 AN XY: 74500

Gnomad4 AFR AF: 0.0000240

Gnomad4 AMR AF: 0.000588

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000241 Hom.: 0

Bravo AF: 0.000249

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000338 AC: 41

EpiCase AF: 0.000273

EpiControl AF: 0.000119

ClinVar

Significance: Benign

Submissions summary: Uncertain:3 Benign:9

Revision: reviewed by expert panel

Submissions by phenotype

not specified Uncertain:1 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 25, 2010	Variant classified as Uncertain Significance - Favor Benign. The Ile185Val varia nt has not previously been reported in the literature or public databases, and i t has not been identified in our laboratory in more than 670 Caucasian probands. This variant was identified in a family member of this individual who is report edly unaffected with the clinical features of Noonan spectrum disorders. This po sition is not highly conserved in evolution, and the frog has a Val at this posi tion of the protein. Finally, this variant is predicted by three different compu tational tools to have a benign role, though it should be noted that the accurac y of these tools is not well understood. Therefore, while the clinical significa nce of this variant cannot be determined conclusively at this time, we lean towa rds it having a benign role. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 24, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Uncertain:1 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 20, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 12, 2017	Variant summary: The c.553G>A (p.Ile185Val) in SOS1 gene is a missense change that involves a non-conserved nucleotide and 5/5 in silico tools predict benign outcome. The variant is located outside of any known functional domain, however no functional studies confirming lack of impact of the variant on the protein function have been reported at the time of evaluation. The variant is present in the large control population datasets of ExAC and gnomAD at a frequency 0.0003395 and 0.0003576, respectively (41/120780 and 88/ 246106 chrs tested, respectively). These frequencies exceed the maximal expected frequency of a pathogenic allele (0.000035) in this gene. The variant has not, to our knowledge, been reported in affected individuals via published reports but cited as Likely Benign by a reputable databases/clinical laboratories. Taking together, the variant was classified as Benign. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 10, 2019	This variant is associated with the following publications: (PMID: 29493581, 31573083) -

RASopathy Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 18, 2024	- -
Benign, reviewed by expert panel	curation	ClinGen RASopathy Variant Curation Expert Panel	Apr 18, 2017	The filtering allele frequency of the c.553A>G (p.Ile185Val) variant in the SOS1 gene is 0.087% (16/11574) of Latino 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) -

Noonan syndrome 4 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 04, 2019

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Fibromatosis, gingival, 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Noonan syndrome and Noonan-related syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jan 01, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.52
Cadd	Benign	12
Dann	Benign	0.78
DEOGEN2	Benign	0.33	T;T;T
Eigen	Benign	-0.93
Eigen_PC	Benign	-0.74
FATHMM_MKL	Benign	0.12	N
M_CAP	Benign	0.050	D
MetaRNN	Benign	0.0050	T;T;T
MetaSVM	Benign	-0.43	T
MutationAssessor	Benign	-1.1	N;N;.
MutationTaster	Benign	0.98	N;N;N;N
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.26	N;N;N
REVEL	Benign	0.14
Sift	Benign	0.37	T;T;T
Sift4G	Benign	0.84	T;T;T
Polyphen		0.0	B;B;.
Vest4		0.071
MVP		0.30
MPC		0.47
ClinPred		0.0066	T
GERP RS		2.5
Varity_R		0.021
gMVP		0.13

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

Publications

LitVar

Other links and lift over

dbSNP: rs143962515; hg19: chr2-39281922;