1-114716090-A-T

Position:

• chr1-114716090-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PS4_Moderate PS3_Supporting PP3 PM2_Supporting PM6_Strong

This summary comes from the ClinGen Evidence Repository: The c.71T>A (p.Ile24Asn) variant in NRAS is a missense variant predicted to cause substitution of isoleucine by asparagine at amino acid 24. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.863, which is above the threshold of 0.7, evidence that correlates with impact to NRAS function (PP3). This variant has been reported in 4 probands with features of RASopathy (PS4_Moderate; PMIDs:21263000, 22855653, 28594414, GeneDx). This variant has been identified as a de novo occurrence with unconfirmed parental relationships in 2 individuals with features of RASopathy (PM6_Strong; PMIDs: 21263000, 22855653). RAS activation assays in 293T cells showed a mild increase in GTP-bound RAS and enhanced MAPK phosphorylation indicating that this variant impacts protein function. A zebrafish model using injected RNA showed developmental and craniofacial defects. The phenotype was completely rescued by MEK inhibition (PMID:21263000)(PS3_Supporting). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal dominant RASopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy VCEP: PM6_Strong, PS4_Moderate, PS3_Supporting, PM2_Supporting, PP3. (RASopathy VCEP specifications version 2.1; 9/17/2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA356968/MONDO:0021060/039

• Frequency: Genomes: not found (cov: 33)
• Consequence: NRAS ENST00000369535.5 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:2 O:1
• Conservation: PhyloP100: 9.32

Genes affected

NRAS (HGNC:7989): (NRAS proto-oncogene, GTPase) This is an N-ras oncogene encoding a membrane protein that shuttles between the Golgi apparatus and the plasma membrane. This shuttling is regulated through palmitoylation and depalmitoylation by the ZDHHC9-GOLGA7 complex. The encoded protein, which has intrinsic GTPase activity, is activated by a guanine nucleotide-exchange factor and inactivated by a GTPase activating protein. Mutations in this gene have been associated with somatic rectal cancer, follicular thyroid cancer, autoimmune lymphoproliferative syndrome, Noonan syndrome, and juvenile myelomonocytic leukemia. [provided by RefSeq, Jun 2011]

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM6: 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/exons	MANE	Protein	UniProt
NRAS	NM_002524.5	c.71T>A	p.Ile24Asn	missense_variant	2/7	ENST00000369535.5	NP_002515.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NRAS	ENST00000369535.5	c.71T>A	p.Ile24Asn	missense_variant	2/7	1	NM_002524.5	ENSP00000358548	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Sep 09, 2021

Published functional studies demonstrate I24N increases MAPK phosphorylation and activation (Runtuwene et al., 2011); Not observed at significant frequency in large population cohorts (Lek et al., 2016); Missense variants in this gene are often considered pathogenic (Stenson et al., 2014); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 21263000, 22855653, 20301303, 28542371, 24939586, 28088512, 23250860, 28098151, 28594414, 27561113, 26467218, 22887781) -

RASopathy Pathogenic:1

Likely pathogenic, reviewed by expert panel

curation

ClinGen RASopathy Variant Curation Expert Panel

Sep 17, 2024

The c.71T>A (p.Ile24Asn) variant in NRAS is a missense variant predicted to cause substitution of isoleucine by asparagine at amino acid 24. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.863, which is above the threshold of 0.7, evidence that correlates with impact to NRAS function (PP3). This variant has been reported in 4 probands with features of RASopathy (PS4_Moderate; PMIDs:21263000, 22855653, 28594414, GeneDx). This variant has been identified as a de novo occurrence with unconfirmed parental relationships in 2 individuals with features of RASopathy (PM6_Strong; PMIDs: 21263000, 22855653). RAS activation assays in 293T cells showed a mild increase in GTP-bound RAS and enhanced MAPK phosphorylation indicating that this variant impacts protein function. A zebrafish model using injected RNA showed developmental and craniofacial defects. The phenotype was completely rescued by MEK inhibition (PMID:21263000)(PS3_Supporting). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal dominant RASopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy VCEP: PM6_Strong, PS4_Moderate, PS3_Supporting, PM2_Supporting, PP3. (RASopathy VCEP specifications version 2.1; 9/17/2024) -

Noonan syndrome 1 Other:1

not provided, no classification provided

literature only

GeneReviews

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.16
CADD	Pathogenic	31
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.72	D
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.87	D
M_CAP	Pathogenic	0.32	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Uncertain	0.39	D
MutationAssessor	Uncertain	2.6	M
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.95	D
PROVEAN	Pathogenic	-5.3	D
REVEL	Pathogenic	0.86
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.012	D
Polyphen		1.0	D
Vest4		0.98
MutPred		0.58		Loss of stability (P = 0.0449);
MVP		0.81
MPC		2.1
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.94
gMVP		0.86

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: rs869025573; hg19: chr1-115258711;