rs760707217

Variant names:

• chr2-39006401-GAAAT-G
• rs760707217
• NM_005633.4:c.2791+7_2791+10delATTT

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP6_Very_Strong BS2

The NM_005633.4(SOS1):​c.2791+7_2791+10delATTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000065 in 1,076,718 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000065 (0 hom.)
• Consequence: SOS1 NM_005633.4 splice_region, intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.24
• Publications: 0 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: Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia, Genomics England PanelApp
• 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
• Noonan syndrome with multiple lentigines

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• Noonan syndrome-like disorder with loose anagen hair

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP6: Variant 2-39006401-GAAAT-G is Benign according to our data. Variant chr2-39006401-GAAAT-G is described in ClinVar as Likely_benign. ClinVar VariationId is 416922.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAdExome4 at 7 AD gene.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SOS1	NM_005633.4	MANE Select	c.2791+7_2791+10delATTT		splice_region intron	N/A	NP_005624.2
	SOS1	NM_001382394.1		c.2770+7_2770+10delATTT		splice_region intron	N/A	NP_001369323.1
	SOS1	NM_001382395.1		c.2791+7_2791+10delATTT		splice_region intron	N/A	NP_001369324.1	G5E9C8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SOS1	ENST00000402219.8	TSL:1 MANE Select	c.2791+7_2791+10delATTT		splice_region intron	N/A	ENSP00000384675.2	Q07889-1
	SOS1	ENST00000395038.6	TSL:5	c.2791+7_2791+10delATTT		splice_region intron	N/A	ENSP00000378479.2	G5E9C8
	SOS1	ENST00000913801.1		c.2671+7_2671+10delATTT		splice_region intron	N/A	ENSP00000583860.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000120 AC: 3 AN: 250198 AF XY: 0.00000739

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000650 AC: 7 AN: 1076718 Hom.: 0 AF XY: 0.00000542 AC XY: 3 AN XY: 553966

African (AFR) AF: 0.00 AC: 0 AN: 26056

American (AMR) AF: 0.0000226 AC: 1 AN: 44200

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23710

East Asian (EAS) AF: 0.000132 AC: 5 AN: 37896

South Asian (SAS) AF: 0.00 AC: 0 AN: 78350

European-Finnish (FIN) AF: 0.0000189 AC: 1 AN: 53030

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4616

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 761214

Other (OTH) AF: 0.00 AC: 0 AN: 47646

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not specified (1)
-	-	1	RASopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.2

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: rs760707217; hg19: chr2-39233542;