2-38997474-GT-GTT

Variant names:

• chr2-38997474-G-GT
• rs869215095
• NM_005633.4:c.2792-50dupA

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_005633.4(SOS1):​c.2792-50dupA variant causes a intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.84 (54883 hom., cov: 0)
  • Exomes 𝑓: 0.92 (476439 hom.)
• Consequence: SOS1 NM_005633.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4 O:1
• Conservation: PhyloP100: 0.245
• Publications: 2 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 -16 ACMG points.

• BP6: Variant 2-38997474-G-GT is Benign according to our data. Variant chr2-38997474-G-GT is described in ClinVar as Benign. ClinVar VariationId is 259847.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.929 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005633.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SOS1	NM_005633.4	MANE Select	c.2792-50dupA		intron	N/A	NP_005624.2
	SOS1	NM_001382394.1		c.2771-50dupA		intron	N/A	NP_001369323.1
	SOS1	NM_001382395.1		c.2792-50dupA		intron	N/A	NP_001369324.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SOS1	ENST00000402219.8	TSL:1 MANE Select	c.2792-50_2792-49insA		intron	N/A	ENSP00000384675.2
	SOS1	ENST00000395038.6	TSL:5	c.2792-50_2792-49insA		intron	N/A	ENSP00000378479.2
	SOS1	ENST00000692089.1		c.2681-50_2681-49insA		intron	N/A	ENSP00000508626.1

Frequencies

GnomAD3 genomes AF: 0.838 AC: 127227 AN: 151860 Hom.: 54857 Cov.: 0

Gnomad AFR AF: 0.616

Gnomad AMI AF: 0.907

Gnomad AMR AF: 0.903

Gnomad ASJ AF: 0.904

Gnomad EAS AF: 0.808

Gnomad SAS AF: 0.830

Gnomad FIN AF: 0.971

Gnomad MID AF: 0.883

Gnomad NFE AF: 0.935

Gnomad OTH AF: 0.854

GnomAD2 exomes AF: 0.892 AC: 208894 AN: 234068 AF XY: 0.893

Gnomad AFR exome AF: 0.608

Gnomad AMR exome AF: 0.938

Gnomad ASJ exome AF: 0.901

Gnomad EAS exome AF: 0.817

Gnomad FIN exome AF: 0.967

Gnomad NFE exome AF: 0.933

Gnomad OTH exome AF: 0.894

GnomAD4 exome AF: 0.915 AC: 1034668 AN: 1130670 Hom.: 476439 Cov.: 17 AF XY: 0.914 AC XY: 528189 AN XY: 578116

African (AFR) AF: 0.598 AC: 16220 AN: 27132

American (AMR) AF: 0.932 AC: 40124 AN: 43030

Ashkenazi Jewish (ASJ) AF: 0.902 AC: 21552 AN: 23902

East Asian (EAS) AF: 0.807 AC: 30612 AN: 37914

South Asian (SAS) AF: 0.845 AC: 66517 AN: 78710

European-Finnish (FIN) AF: 0.966 AC: 43458 AN: 45010

Middle Eastern (MID) AF: 0.866 AC: 4372 AN: 5048

European-Non Finnish (NFE) AF: 0.936 AC: 767641 AN: 820460

Other (OTH) AF: 0.893 AC: 44172 AN: 49464

GnomAD4 genome AF: 0.838 AC: 127299 AN: 151978 Hom.: 54883 Cov.: 0 AF XY: 0.838 AC XY: 62293 AN XY: 74314

African (AFR) AF: 0.616 AC: 25491 AN: 41380

American (AMR) AF: 0.904 AC: 13804 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.904 AC: 3136 AN: 3470

East Asian (EAS) AF: 0.808 AC: 4174 AN: 5166

South Asian (SAS) AF: 0.831 AC: 4002 AN: 4814

European-Finnish (FIN) AF: 0.971 AC: 10249 AN: 10558

Middle Eastern (MID) AF: 0.881 AC: 259 AN: 294

European-Non Finnish (NFE) AF: 0.935 AC: 63559 AN: 68002

Other (OTH) AF: 0.855 AC: 1800 AN: 2106

Alfa AF: 0.888 Hom.: 7073

Bravo AF: 0.819

Asia WGS AF: 0.819 AC: 2840 AN: 3466

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Fibromatosis, gingival, 1 (1)
-	-	1	Noonan syndrome 4 (1)
-	-	1	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.24
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs869215095; hg19: chr2-39224615;