rs113954997

Variant names:

• chr11-14294844-T-A
• rs113954997
• NM_012250.6:c.215A>T

Your query was ambiguous. Multiple possible variants found:

• chr11-14294844-T-A
• chr11-14294844-T-C
• chr11-14294844-T-G

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PS3_Moderate PS4_Supporting PM2_Supporting PP3 PM1 PS2

This summary comes from the ClinGen Evidence Repository: The c.215A>T (p.Gln72Leu) variant in RRAS2 is a missense variant predicted to cause substitution of glutamine by leucine at amino acid 72. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.918, which is above the threshold of 0.7, evidence that correlates with impact to RRAS2 function (PP3). This variant resides within the Switch II domain (amino acids 68 – 75) of RRAS2 that is defined as a critical functional domain by the ClinGen RASopathy VCEP (PM1). This variant has been reported in 2 probands with features of RASopathy (PS4_Supporting; PMID:31130285, 33686258). This variant has been identified as a de novo occurrence with confirmed parental relationships in 2 individuals with features of RASopathy (PS2_VeryStrong; PMID:31130285, 33686258). Pull-down assays with the Raf-Ras-binding domain (RBD, residues 1–149) of RAF1 in HEK293 cells showed increased binding of activated RAS indicating that this variant impacts protein function. Similar results were seen in an immunoblotting assay of the cell lysates expressing WT/variant RRAS2 using anti-phospho-MEK1/2 and phospho-ERK1/2 antibodies. Additionally, Zebrafish embryos injected with variant mRNA showed significantly increased ceratohyal angles compared to the uninjected controls (PMID:31130285)(PS3_Moderate). In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant RASopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy VCEP: PS2_VeryStrong, PS3_Moderate, PM1, PS4_Supporting, PM2_Supporting, PP3. (RASopathy VCEP specifications version 1.1; 9/17/2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA120437/MONDO:0018997/127

• Frequency: Genomes: not found (cov: 32)
• Consequence: RRAS2 NM_012250.6 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:6
• Conservation: PhyloP100: 7.97
• Publications: 42 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: ClinGen, Orphanet
• noonan syndrome 12

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

  Inheritance: Unknown Classification: NO_KNOWN Submitted by: Ambry Genetics

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PS2: For more information check the summary or visit ClinGen Evidence Repository.
• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012250.6. 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
	RRAS2	NM_012250.6	MANE Select	c.215A>T	p.Gln72Leu	missense	Exon 3 of 6	NP_036382.2
	RRAS2	NM_001440708.1		c.215A>T	p.Gln72Leu	missense	Exon 3 of 7	NP_001427637.1
	RRAS2	NM_001177314.2		c.110A>T	p.Gln37Leu	missense	Exon 3 of 6	NP_001170785.1	P62070-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RRAS2	ENST00000256196.9	TSL:1 MANE Select	c.215A>T	p.Gln72Leu	missense	Exon 3 of 6	ENSP00000256196.4	P62070-1
	RRAS2	ENST00000526063.5	TSL:1	c.-17A>T		5_prime_UTR	Exon 3 of 6	ENSP00000434104.1	P62070-2
	RRAS2	ENST00000532814.5	TSL:1	c.-17A>T		5_prime_UTR	Exon 3 of 6	ENSP00000431954.1	P62070-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
3	-	-	Noonan syndrome 12 (3)
2	-	-	Noonan syndrome (2)
1	-	-	Ovarian neoplasm (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.39
CADD	Pathogenic	30
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.75	D
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.83	T
M_CAP	Pathogenic	0.30	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Pathogenic	0.89	D
MutationAssessor	Pathogenic	3.2	M
PhyloP100		8.0
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-6.8	D
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.95	P
Vest4		0.75
MutPred		0.76		Gain of stability (P = 0.0197)
MVP		0.90
MPC		1.2
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.93
gMVP		0.68
Mutation Taster		=108/192	disease causing (ClinVar)

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: rs113954997; hg19: chr11-14316390; COSMIC: COSV56329169;