rs765097073

Variant names:

• chr14-50118794-TGGA-T
• rs765097073
• NM_006939.4:c.3546_3548delTCC

Your query was ambiguous. Multiple possible variants found:

• chr14-50118794-TGGA-T
• chr14-50118794-TGGA-TGGAGGA

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 1P and 4B. PM4_Supporting BS2

The NM_006939.4(SOS2):​c.3546_3548delTCC​(p.Pro1183del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.00000993 in 1,410,218 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000099 (1 hom.)
• Consequence: SOS2 NM_006939.4 disruptive_inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.60
• Publications: 0 publications found

Genes affected

SOS2 (HGNC:11188): (SOS Ras/Rho guanine nucleotide exchange factor 2) This gene encodes a regulatory protein that is involved in the positive regulation of ras proteins. Mutations in this gene are associated with Noonan Syndrome-9. [provided by RefSeq, Jul 2016]

SOS2 Gene-Disease associations (from GenCC):

• Noonan syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• Noonan syndrome 9

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia, G2P

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_006939.4. Strenght limited to Supporting due to length of the change: 1aa.
• BS2: High AC in GnomAdExome4 at 14 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SOS2	NM_006939.4	c.3546_3548delTCC	p.Pro1183del	disruptive_inframe_deletion	Exon 23 of 23	ENST00000216373.10	NP_008870.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SOS2	ENST00000216373.10	c.3546_3548delTCC	p.Pro1183del	disruptive_inframe_deletion	Exon 23 of 23	1	NM_006939.4	ENSP00000216373.5
SOS2	ENST00000543680.5	c.3447_3449delTCC	p.Pro1150del	disruptive_inframe_deletion	Exon 22 of 22	1		ENSP00000445328.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD2 exomes AF: 0.0000173 AC: 4 AN: 230798 AF XY: 0.0000159

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000993 AC: 14 AN: 1410218 Hom.: 1 AF XY: 0.0000129 AC XY: 9 AN XY: 697792

African (AFR) AF: 0.00 AC: 0 AN: 32226

American (AMR) AF: 0.00 AC: 0 AN: 40592

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24602

East Asian (EAS) AF: 0.00 AC: 0 AN: 38316

South Asian (SAS) AF: 0.000149 AC: 12 AN: 80546

European-Finnish (FIN) AF: 0.0000193 AC: 1 AN: 51842

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5540

European-Non Finnish (NFE) AF: 9.27e-7 AC: 1 AN: 1078820

Other (OTH) AF: 0.00 AC: 0 AN: 57734

GnomAD4 genome Cov.: 30

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Noonan syndrome 9 Uncertain:1

Feb 24, 2020

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.6

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs765097073; hg19: chr14-50585512;