Variant 1-114713908-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PM5PP3_ModeratePP5_Very_Strong

The NM_002524.5(NRAS):c.182A>G(p.Gln61Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q61H) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

NRAS
NM_002524.5 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:12O:1

Conservation

PhyloP100: 7.91

Variant links:

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]

NRAS links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_002524.5

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-114713908-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 280409.Status of the report is criteria_provided_single_submitter, 1 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.876

PP5

Variant 1-114713908-T-C is Pathogenic according to our data. Variant chr1-114713908-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 13900.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-114713908-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NRAS	NM_002524.5 linkuse as main transcript	c.182A>G	p.Gln61Arg	missense_variant	3/7	ENST00000369535.5	NP_002515.1	P01111Q5U091

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NRAS	ENST00000369535.5 linkuse as main transcript	c.182A>G	p.Gln61Arg	missense_variant	3/7	1	NM_002524.5	ENSP00000358548.4		P01111

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:12Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:4

Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 18, 2023	Published functional studies demonstrate increased levels of Nras-GTP (Kong et al., 2016) and constitutive activation of the MAPK pathway (Demin et al., 2019); Not observed at significant frequency in large population cohorts (gnomAD); The majority of missense variants in this gene are considered pathogenic (HGMD); 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: 6587382, 14508525, 19880792, 25142146, 22773810, 1654209, 29883661, 18633438, 23392294, 24006476, 20526288, 24077912, 27109513, 31228933, 23855428, 22237106, 17910045) -
Pathogenic, criteria provided, single submitter	clinical testing	Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital	Sep 03, 2021	This is a recurrent pathogenic variant that has been reported previously in multiple individuals with kaposiform lymphangiomatosis (KLA), as well as an individual with a generalized lymphatic anomaly (GLA), also known as diffuse lymphangiomatosis (PMID: 30542204, PMID: 31511039, PMID: 29397482). This change is also reported as an oncogenic variant found in multiple tumor types, especially melanoma (COSMIC and cBioPortal Databases). This variant is not present in large population cohorts (Genome Aggregation Database v2.1.1). The p.Gln61Arg variant leads to constitutive activation of the NRAS protein (PMID: 30542204, PMID: 29397482). -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Large congenital melanocytic nevus

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genomics Laboratory, Washington University in St. Louis	Oct 14, 2023	The NRAS c.182A>G (p.Gln61Arg) variant was identified at an allelic fraction consistent with somatic origin. This variant has been reported in multiple individuals with melanocytic nevus (Kinsler VA et al., PMID: 23392294; Abdulmajid L et al., PMID: 34255877; Francis JH et al., PMID: 29332123; Colebatch AJ et al., PMID: 30772300; Tschandl P et al., PMID: 23861977; Dessars B et al., PMID: 18633438). This variant has been reported in the ClinVar database as a pathogenic variant by multiple submitters (ClinVar ID: 13900) and in multiple cancer cases as a somatic variant in the cancer database COSMIC (COSMIC ID: COSV54736340). This variant is absent from the general population (gnomAD v.3.1.2), indicating it is not a common variant. The same amino acid change (p.Gln61Arg), resulting from a different nucleotide change, c.182_183delinsGG, has been reported in melanoma and is considered pathogenic (Ball NJ et al., PMID: 8120410; ClinVar ID: 375873). The NRAS c.182A>G (p.Gln61Arg) variant resides within a GTP-binding site of NRAS that is defined as a critical function domain (Scheffzek K et al., PMID: 9219684). Computational predictors indicate that the variant is damaging, evidence that correlates with impact on NRAS function. In support of this prediction, functional studies show that this variant impairs the GTPase activity and activates Ras/Raf/MEK/MAPK pathway, leading to cellular transformation (Ross AL et al., PMID: 21754924; Ruan Y et al., PMID: 25395461). The NRAS gene is defined by the ClinGen's RASopathy expert panel as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (Gelb BD et al., PMID: 29493581). Based on an internally developed protocol informed by the ACMG/AMP guidelines (Richards S et al., PMID: 25741868) and gene-specific practices from the ClinGen Criteria Specification Registry, the NRAS c.182A>G (p.Gln61Arg) variant is classified as pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 15, 2014	- -

Thyroid cancer, nonmedullary, 2

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 15, 2014

- -

Linear nevus sebaceous syndrome

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 15, 2014

- -

Epidermal nevus

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 15, 2014

- -

Noonan syndrome 6

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center

Oct 07, 2024

- -

Non-small cell lung carcinoma

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Aug 12, 2011

- -

Neurocutaneous melanocytosis

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 15, 2014

- -

Neoplasm

Other:1

-, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Jul 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.43

BayesDel_noAF

Pathogenic

0.38

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.69

Eigen

Uncertain

0.46

Eigen_PC

Uncertain

0.51

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.92

M_CAP

Uncertain

0.11

MetaRNN

Pathogenic

0.88

MetaSVM

Uncertain

0.29

MutationAssessor

Pathogenic

3.3

PrimateAI

Pathogenic

0.88

PROVEAN

Uncertain

-3.4

REVEL

Pathogenic

0.89

Sift

Uncertain

0.029

Sift4G

Uncertain

0.048

Polyphen

0.21

Vest4

0.80

MutPred

0.75

Loss of glycosylation at T58 (P = 0.1035);

MVP

0.97

MPC

0.99

ClinPred

0.98

GERP RS

5.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.84

gMVP

0.83

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over