2-39054589-G-C

Position:

• chr2-39054589-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005633.4(SOS1):​c.720+25C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.912 in 1,272,808 control chromosomes in the GnomAD database, including 530,808 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.92 (65075 hom., cov: 32)
  • Exomes 𝑓: 0.91 (465733 hom.)
• Consequence: SOS1 NM_005633.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5 O:1
• Conservation: PhyloP100: -0.808

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 2-39054589-G-C is Benign according to our data. Variant chr2-39054589-G-C is described in ClinVar as [Benign]. Clinvar id is 180179.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.963 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SOS1	NM_005633.4	c.720+25C>G		intron_variant		ENST00000402219.8	NP_005624.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SOS1	ENST00000402219.8	c.720+25C>G		intron_variant		1	NM_005633.4	ENSP00000384675.2

Frequencies

GnomAD3 genomes AF: 0.924 AC: 140519 AN: 152132 Hom.: 65015 Cov.: 32

Gnomad AFR AF: 0.971

Gnomad AMI AF: 0.906

Gnomad AMR AF: 0.904

Gnomad ASJ AF: 0.891

Gnomad EAS AF: 0.818

Gnomad SAS AF: 0.826

Gnomad FIN AF: 0.913

Gnomad MID AF: 0.899

Gnomad NFE AF: 0.919

Gnomad OTH AF: 0.910

GnomAD3 exomes AF: 0.902 AC: 222952 AN: 247126 Hom.: 100892 AF XY: 0.897 AC XY: 119992 AN XY: 133774

Gnomad AFR exome AF: 0.971

Gnomad AMR exome AF: 0.931

Gnomad ASJ exome AF: 0.887

Gnomad EAS exome AF: 0.828

Gnomad SAS exome AF: 0.833

Gnomad FIN exome AF: 0.906

Gnomad NFE exome AF: 0.916

Gnomad OTH exome AF: 0.890

GnomAD4 exome AF: 0.911 AC: 1020792 AN: 1120560 Hom.: 465733 Cov.: 15 AF XY: 0.908 AC XY: 520677 AN XY: 573434

Gnomad4 AFR exome AF: 0.973

Gnomad4 AMR exome AF: 0.927

Gnomad4 ASJ exome AF: 0.888

Gnomad4 EAS exome AF: 0.822

Gnomad4 SAS exome AF: 0.839

Gnomad4 FIN exome AF: 0.910

Gnomad4 NFE exome AF: 0.921

Gnomad4 OTH exome AF: 0.901

GnomAD4 genome AF: 0.924 AC: 140638 AN: 152248 Hom.: 65075 Cov.: 32 AF XY: 0.920 AC XY: 68446 AN XY: 74438

Gnomad4 AFR AF: 0.971

Gnomad4 AMR AF: 0.904

Gnomad4 ASJ AF: 0.891

Gnomad4 EAS AF: 0.819

Gnomad4 SAS AF: 0.827

Gnomad4 FIN AF: 0.913

Gnomad4 NFE AF: 0.919

Gnomad4 OTH AF: 0.910

Alfa AF: 0.917 Hom.: 11292

Bravo AF: 0.927

Asia WGS AF: 0.843 AC: 2927 AN: 3468

ClinVar

Significance: Benign

Submissions summary: Benign:5 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2 Other:1

not provided, no classification provided	phenotyping only	GenomeConnect - CFC International	-	Variant interpreted as Benign and reported on 04-30-2009 by Lab or GTR ID 239772. GenomeConnect-CFC International assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 23, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Noonan syndrome 4 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 15, 2021

- -

Noonan syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Mar 03, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.13
DANN	Benign	0.44
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs997344; hg19: chr2-39281730;