NM_005633.4:c.2792-51_2792-50dupAA

Variant names:

• chr2-38997474-G-GTT
• rs869215095
• NM_005633.4:c.2792-51_2792-50dupAA

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_005633.4(SOS1):​c.2792-51_2792-50dupAA variant causes a intron change involving the alteration of a non-conserved nucleotide. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 0)
  • Exomes 𝑓: 0.000050 (0 hom.)
• Consequence: SOS1 NM_005633.4 intron
• Clinical Significance: Not reported in ClinVar
• 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: Uncertain_significance. The variant received 0 ACMG points.

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.2792-51_2792-50dupAA		intron	N/A	NP_005624.2
	SOS1	NM_001382394.1		c.2771-51_2771-50dupAA		intron	N/A	NP_001369323.1
	SOS1	NM_001382395.1		c.2792-51_2792-50dupAA		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_2792-49insAA		intron	N/A	ENSP00000384675.2
	SOS1	ENST00000395038.6	TSL:5	c.2792-50_2792-49insAA		intron	N/A	ENSP00000378479.2
	SOS1	ENST00000692089.1		c.2681-50_2681-49insAA		intron	N/A	ENSP00000508626.1

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151898 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000480

GnomAD2 exomes AF: 0.0000214 AC: 5 AN: 234068 AF XY: 0.0000235

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000602

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000122

Gnomad NFE exome AF: 0.00000937

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000504 AC: 57 AN: 1130970 Hom.: 0 Cov.: 17 AF XY: 0.0000536 AC XY: 31 AN XY: 578286

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 27168

American (AMR) AF: 0.0000697 AC: 3 AN: 43034

Ashkenazi Jewish (ASJ) AF: 0.0000418 AC: 1 AN: 23906

East Asian (EAS) AF: 0.00 AC: 0 AN: 37928

South Asian (SAS) AF: 0.0000635 AC: 5 AN: 78744

European-Finnish (FIN) AF: 0.0000889 AC: 4 AN: 45008

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5050

European-Non Finnish (NFE) AF: 0.0000512 AC: 42 AN: 820662

Other (OTH) AF: 0.0000404 AC: 2 AN: 49470

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151898 Hom.: 0 Cov.: 0 AF XY: 0.0000270 AC XY: 2 AN XY: 74200

African (AFR) AF: 0.00 AC: 0 AN: 41292

American (AMR) AF: 0.00 AC: 0 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10558

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68010

Other (OTH) AF: 0.000480 AC: 1 AN: 2084

Alfa AF: 0.00 Hom.: 7073

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.24

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs869215095; hg19: chr2-39224615;