11-14294372-ATTTT-ATTTTTTTTTTT

Variant names:

• chr11-14294372-A-ATTTTTTT
• rs5789833
• NM_012250.6:c.408+92_408+98dupAAAAAAA

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_012250.6(RRAS2):​c.408+92_408+98dupAAAAAAA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000242 in 413,880 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 0)
  • Exomes 𝑓: 0.0000024 (0 hom.)
• Consequence: RRAS2 NM_012250.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.148
• Publications: 0 publications found

Genes affected

RRAS2 (HGNC:17271): (RAS related 2) This gene encodes a member of the R-Ras subfamily of Ras-like small GTPases. The encoded protein associates with the plasma membrane and may function as a signal transducer. This protein may play an important role in activating signal transduction pathways that control cell proliferation. Mutations in this gene are associated with the growth of certain tumors. Pseudogenes of this gene are found on chromosomes 1 and 2. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Apr 2010]

RRAS2 Gene-Disease associations (from GenCC):

• Noonan syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• noonan syndrome 12

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

  Inheritance: Unknown Classification: NO_KNOWN Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RRAS2	NM_012250.6	c.408+92_408+98dupAAAAAAA		intron_variant	Intron 4 of 5	ENST00000256196.9	NP_036382.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RRAS2	ENST00000256196.9	c.408+98_408+99insAAAAAAA		intron_variant	Intron 4 of 5	1	NM_012250.6	ENSP00000256196.4

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD4 exome AF: 0.00000242 AC: 1 AN: 413880 Hom.: 0 AF XY: 0.00000471 AC XY: 1 AN XY: 212256

⚠️ 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: 10738

American (AMR) AF: 0.00 AC: 0 AN: 9952

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 9676

East Asian (EAS) AF: 0.00 AC: 0 AN: 21280

South Asian (SAS) AF: 0.00 AC: 0 AN: 24478

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 30784

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1520

European-Non Finnish (NFE) AF: 0.00000351 AC: 1 AN: 284708

Other (OTH) AF: 0.00 AC: 0 AN: 20744

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.15

Splicing

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

Other links and lift over

dbSNP: rs5789833; hg19: chr11-14315918;