rs1454223

Variant names:

• chr2-38997210-G-T
• rs1454223
• NM_005633.4:c.2964+43C>A

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.2964+43C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.93 in 1,491,398 control chromosomes in the GnomAD database, including 645,815 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.94 (67001 hom., cov: 33)
  • Exomes 𝑓: 0.93 (578814 hom.)
• Consequence: SOS1 NM_005633.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4 O:1
• Conservation: PhyloP100: -0.745

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 (BayesDel_noAF=-0.91).
• BP6: Variant 2-38997210-G-T is Benign according to our data. Variant chr2-38997210-G-T is described in ClinVar as [Benign]. Clinvar id is 259848.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.954 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SOS1	NM_005633.4	c.2964+43C>A		intron_variant	Intron 18 of 22	ENST00000402219.8	NP_005624.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SOS1	ENST00000402219.8	c.2964+43C>A		intron_variant	Intron 18 of 22	1	NM_005633.4	ENSP00000384675.2

Frequencies

GnomAD3 genomes AF: 0.937 AC: 142607 AN: 152154 Hom.: 66941 Cov.: 33

Gnomad AFR AF: 0.962

Gnomad AMI AF: 0.906

Gnomad AMR AF: 0.941

Gnomad ASJ AF: 0.907

Gnomad EAS AF: 0.815

Gnomad SAS AF: 0.834

Gnomad FIN AF: 0.972

Gnomad MID AF: 0.908

Gnomad NFE AF: 0.935

Gnomad OTH AF: 0.923

GnomAD3 exomes AF: 0.921 AC: 225352 AN: 244650 Hom.: 104132 AF XY: 0.915 AC XY: 121474 AN XY: 132686

Gnomad AFR exome AF: 0.963

Gnomad AMR exome AF: 0.958

Gnomad ASJ exome AF: 0.904

Gnomad EAS exome AF: 0.824

Gnomad SAS exome AF: 0.843

Gnomad FIN exome AF: 0.968

Gnomad NFE exome AF: 0.934

Gnomad OTH exome AF: 0.911

GnomAD4 exome AF: 0.929 AC: 1244232 AN: 1339126 Hom.: 578814 Cov.: 19 AF XY: 0.926 AC XY: 622513 AN XY: 672056

Gnomad4 AFR exome AF: 0.963

Gnomad4 AMR exome AF: 0.955

Gnomad4 ASJ exome AF: 0.906

Gnomad4 EAS exome AF: 0.820

Gnomad4 SAS exome AF: 0.849

Gnomad4 FIN exome AF: 0.967

Gnomad4 NFE exome AF: 0.937

Gnomad4 OTH exome AF: 0.918

GnomAD4 genome AF: 0.937 AC: 142727 AN: 152272 Hom.: 67001 Cov.: 33 AF XY: 0.935 AC XY: 69621 AN XY: 74460

Gnomad4 AFR AF: 0.962

Gnomad4 AMR AF: 0.941

Gnomad4 ASJ AF: 0.907

Gnomad4 EAS AF: 0.815

Gnomad4 SAS AF: 0.835

Gnomad4 FIN AF: 0.972

Gnomad4 NFE AF: 0.935

Gnomad4 OTH AF: 0.922

Alfa AF: 0.934 Hom.: 13632

Bravo AF: 0.937

Asia WGS AF: 0.847 AC: 2940 AN: 3468

ClinVar

Significance: Benign

Submissions summary: Benign:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2 Other:1

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GenomeConnect - CFC International

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

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. -

Jun 23, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

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PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Noonan syndrome 4 Benign:1

Jul 15, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.79
DANN	Benign	0.39

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: rs1454223; hg19: chr2-39224351;