rs2290445

Variant names:

• chr2-38987680-A-C
• rs2290445
• NM_005633.4:c.3392-89T>G

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005633.4(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 NM_005633.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0120
• Publications: 8 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: Genomics England PanelApp, G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• 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

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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 rank	MANE	Protein	UniProt
SOS1	NM_005633.4	c.3392-89T>G		intron_variant	Intron 21 of 22	ENST00000402219.8	NP_005624.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SOS1	ENST00000402219.8	c.3392-89T>G		intron_variant	Intron 21 of 22	1	NM_005633.4	ENSP00000384675.2

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

African (AFR) AF: 0.961 AC: 15461 AN: 16090

American (AMR) AF: 0.953 AC: 32707 AN: 34322

Ashkenazi Jewish (ASJ) AF: 0.904 AC: 18198 AN: 20120

East Asian (EAS) AF: 0.827 AC: 26733 AN: 32314

South Asian (SAS) AF: 0.855 AC: 53201 AN: 62192

European-Finnish (FIN) AF: 0.967 AC: 38309 AN: 39616

Middle Eastern (MID) AF: 0.871 AC: 2429 AN: 2788

European-Non Finnish (NFE) AF: 0.937 AC: 318017 AN: 339570

Other (OTH) AF: 0.919 AC: 28557 AN: 31078

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

African (AFR) AF: 0.961 AC: 39915 AN: 41554

American (AMR) AF: 0.940 AC: 14371 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.907 AC: 3150 AN: 3472

East Asian (EAS) AF: 0.820 AC: 4249 AN: 5180

South Asian (SAS) AF: 0.837 AC: 4042 AN: 4828

European-Finnish (FIN) AF: 0.972 AC: 10318 AN: 10618

Middle Eastern (MID) AF: 0.905 AC: 266 AN: 294

European-Non Finnish (NFE) AF: 0.936 AC: 63672 AN: 68032

Other (OTH) AF: 0.923 AC: 1953 AN: 2116

Alfa AF: 0.940 Hom.: 25456

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

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 23, 2018

GeneDx

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	-0.85
CADD	Benign	8.3
DANN	Benign	0.61
PhyloP100		0.012
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2290445; hg19: chr2-39214821;