chr3-141487089-G-GGCGGCGGCGCCTGCTGCTGCGGCGGCGCCTGCTGCT

Variant names:

• chr3-141487089-G-GGCGGCGGCGCCTGCTGCTGCGGCGGCGCCTGCTGCT
• rs769524904
• NM_006506.5:c.32_33insGCCTGCTGCTGCGGCGGCGCCTGCTGCTGCGGCGGC

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM4

The NM_006506.5(RASA2):​c.32_33insGCCTGCTGCTGCGGCGGCGCCTGCTGCTGCGGCGGC​(p.Ala11_Ser12insProAlaAlaAlaAlaAlaProAlaAlaAlaAlaAla) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000822 in 1,217,124 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 8.2e-7 (0 hom.)
• Consequence: RASA2 NM_006506.5 disruptive_inframe_insertion
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.08
• Publications: 0 publications found

Genes affected

RASA2 (HGNC:9872): (RAS p21 protein activator 2) The protein encoded by this gene is member of the GAP1 family of GTPase-activating proteins. The gene product stimulates the GTPase activity of normal RAS p21 but not its oncogenic counterpart. Acting as a suppressor of RAS function, the protein enhances the weak intrinsic GTPase activity of RAS proteins resulting in the inactive GDP-bound form of RAS, thereby allowing control of cellular proliferation and differentiation. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2014]

RASA2 Gene-Disease associations (from GenCC):

• Noonan syndrome

  Inheritance: AD Classification: SUPPORTIVE, LIMITED Submitted by: ClinGen, 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: Uncertain_significance. The variant received 2 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_006506.5.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006506.5. 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
	RASA2	NM_006506.5	MANE Select	c.32_33insGCCTGCTGCTGCGGCGGCGCCTGCTGCTGCGGCGGC	p.Ala11_Ser12insProAlaAlaAlaAlaAlaProAlaAlaAlaAlaAla	disruptive_inframe_insertion	Exon 1 of 24	NP_006497.2
	RASA2	NM_001303246.3		c.32_33insGCCTGCTGCTGCGGCGGCGCCTGCTGCTGCGGCGGC	p.Ala11_Ser12insProAlaAlaAlaAlaAlaProAlaAlaAlaAlaAla	disruptive_inframe_insertion	Exon 1 of 25	NP_001290175.1
	RASA2	NM_001303245.3		c.32_33insGCCTGCTGCTGCGGCGGCGCCTGCTGCTGCGGCGGC	p.Ala11_Ser12insProAlaAlaAlaAlaAlaProAlaAlaAlaAlaAla	disruptive_inframe_insertion	Exon 1 of 24	NP_001290174.1	Q15283-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RASA2	ENST00000286364.9	TSL:1 MANE Select	c.32_33insGCCTGCTGCTGCGGCGGCGCCTGCTGCTGCGGCGGC	p.Ala11_Ser12insProAlaAlaAlaAlaAlaProAlaAlaAlaAlaAla	disruptive_inframe_insertion	Exon 1 of 24	ENSP00000286364.3	Q15283-2
	RASA2	ENST00000930693.1		c.32_33insGCCTGCTGCTGCGGCGGCGCCTGCTGCTGCGGCGGC	p.Ala11_Ser12insProAlaAlaAlaAlaAlaProAlaAlaAlaAlaAla	disruptive_inframe_insertion	Exon 1 of 25	ENSP00000600752.1
	RASA2	ENST00000950127.1		c.32_33insGCCTGCTGCTGCGGCGGCGCCTGCTGCTGCGGCGGC	p.Ala11_Ser12insProAlaAlaAlaAlaAlaProAlaAlaAlaAlaAla	disruptive_inframe_insertion	Exon 1 of 25	ENSP00000620186.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 8.22e-7 AC: 1 AN: 1217124 Hom.: 0 Cov.: 30 AF XY: 0.00000167 AC XY: 1 AN XY: 597624

African (AFR) AF: 0.00 AC: 0 AN: 24116

American (AMR) AF: 0.00 AC: 0 AN: 18272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17680

East Asian (EAS) AF: 0.00 AC: 0 AN: 24216

South Asian (SAS) AF: 0.00 AC: 0 AN: 60000

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 42302

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3342

European-Non Finnish (NFE) AF: 0.00000102 AC: 1 AN: 979672

Other (OTH) AF: 0.00 AC: 0 AN: 47524

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.1

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs769524904; hg19: chr3-141205931;