rs2290445

Positions:

• chr2-38987680-A-C
• chr2-38987680-A-G
• chr2-38987680-A-T

Variant summary

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

The ENST00000402219.8(SOS1):​c.3392-89T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.926 in 730,386 control chromosomes in the GnomAD database, including 313,814 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.94 (67010 hom., cov: 33)
  • Exomes 𝑓: 0.92 (246804 hom.)
• Consequence: SOS1 ENST00000402219.8 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0120

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=-0.85).
• BP6: Variant 2-38987680-A-C is Benign according to our data. Variant chr2-38987680-A-C is described in ClinVar as [Benign]. Clinvar id is 1291489.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.953 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SOS1	NM_005633.4	c.3392-89T>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.3392-89T>G		intron_variant		1	NM_005633.4	ENSP00000384675	A1

Frequencies

GnomAD3 genomes AF: 0.937 AC: 142649 AN: 152178 Hom.: 66956 Cov.: 33

Gnomad AFR AF: 0.961

Gnomad AMI AF: 0.906

Gnomad AMR AF: 0.940

Gnomad ASJ AF: 0.907

Gnomad EAS AF: 0.820

Gnomad SAS AF: 0.837

Gnomad FIN AF: 0.972

Gnomad MID AF: 0.908

Gnomad NFE AF: 0.936

Gnomad OTH AF: 0.923

GnomAD4 exome AF: 0.923 AC: 533612 AN: 578090 Hom.: 246804 Cov.: 6 AF XY: 0.919 AC XY: 286577 AN XY: 311868

Gnomad4 AFR exome AF: 0.961

Gnomad4 AMR exome AF: 0.953

Gnomad4 ASJ exome AF: 0.904

Gnomad4 EAS exome AF: 0.827

Gnomad4 SAS exome AF: 0.855

Gnomad4 FIN exome AF: 0.967

Gnomad4 NFE exome AF: 0.937

Gnomad4 OTH exome AF: 0.919

GnomAD4 genome AF: 0.937 AC: 142762 AN: 152296 Hom.: 67010 Cov.: 33 AF XY: 0.935 AC XY: 69633 AN XY: 74460

Gnomad4 AFR AF: 0.961

Gnomad4 AMR AF: 0.940

Gnomad4 ASJ AF: 0.907

Gnomad4 EAS AF: 0.820

Gnomad4 SAS AF: 0.837

Gnomad4 FIN AF: 0.972

Gnomad4 NFE AF: 0.936

Gnomad4 OTH AF: 0.923

Alfa AF: 0.939 Hom.: 15789

Bravo AF: 0.937

Asia WGS AF: 0.852 AC: 2965 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 23, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	8.3
DANN	Benign	0.61

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: rs2290445; hg19: chr2-39214821;