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. Variant got 11 ACMG points: 11P and 0B. PP3 PM1 PS3_Moderate PS4_Supporting PM2_Supporting 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

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]

ACMG classification

Verdict is Pathogenic. Variant got 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RRAS2	NM_012250.6	c.215A>T	p.Gln72Leu	missense_variant	Exon 3 of 6	ENST00000256196.9	NP_036382.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RRAS2	ENST00000256196.9	c.215A>T	p.Gln72Leu	missense_variant	Exon 3 of 6	1	NM_012250.6	ENSP00000256196.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: reviewed by expert panel

Submissions by phenotype

Noonan syndrome 12 Pathogenic:3

Aug 02, 1994

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

May 28, 2020

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -

Jul 07, 2020

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Noonan syndrome Pathogenic:2

Apr 01, 2019

Tartaglia Lab, Genetics and Rare Diseases Research Division, Bambino Gesu' Children's Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

this is a pathogenic variant associated with Noonan Syndrome -

Sep 17, 2024

ClinGen RASopathy Variant Curation Expert Panel

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

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) -

Ovarian neoplasm Pathogenic:1

Aug 02, 1994

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

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;T;T
M_CAP	Pathogenic	0.30	D
MetaRNN	Pathogenic	0.93	D;D;D
MetaSVM	Pathogenic	0.89	D
MutationAssessor	Pathogenic	3.2	.;M;.
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-6.8	D;D;D
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;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

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

Publications

LitVar

Other links and lift over

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