1-114716126-C-T

Position:

chr1-114716126-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM5PP3_ModeratePP5_Very_Strong

The ENST00000369535.5(NRAS):c.35G>A(p.Gly12Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000105 in 1,613,956 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G12F) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000010 ( 0 hom. )

Consequence

NRAS
ENST00000369535.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 3 uncertain in ENST00000369535.5

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-114716126-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 219097.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.914

PP5

Variant 1-114716126-C-T is Pathogenic according to our data. Variant chr1-114716126-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 39648.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-114716126-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NRAS	NM_002524.5 linkuse as main transcript	c.35G>A	p.Gly12Asp	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 linkuse as main transcript	c.35G>A	p.Gly12Asp	missense_variant	2/7	1	NM_002524.5	ENSP00000358548	P1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152154

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000795

AC:

AN:

251484

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135916

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000103

AC:

AN:

1461684

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

727132

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000117

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152272

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74456

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000847

Hom.:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	May 27, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Jul 22, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 16, 2021	Published functional studies suggest the variant promotes oncogenesis/leukemogenesis (Haigis et al., 2008; Wang et al., 2011; Wang et al., 2013); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variants in this gene are often considered pathogenic (HGMD); This variant is associated with the following publications: (PMID: 21586752, 23687087, 26090869, 22753870, 15517309, 23303902, 31031743, 28594414, 14982869, 18372904) -

Noonan syndrome 6

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	New York Genome Center	Mar 26, 2021	The de novo heterozygous c.35G>A (p.Gly12Asp) variant identified in the NRAS gene is a known disease-causing variant and has been reported in ClinVar a Pathogenic by multiple independent laboratories [Variation ID:39648]. Other missense variants affecting the same residue Gly12 have been reported as somatic variants in different types of cancers. The c.35G>A (p.Gly12Asp) variant identified in this individual has been reported as a somatic variant in different types of cancers [ClinVar Variation ID:39648], as well as a de novo germline variant in a patient with Noonan syndrome [for detailed clinical description see Patient# 13 in PMID: 28594414]. The variant has 0.00001314 allele frequency in the gnomAD(v3) database (2 out of 152154 heterozygous alleles, no homozygotes) suggesting it is not a common benign allele in the populations represented in that database. The variant affects a highly conserved residue and is predicted deleterious by multiple in silico tools [CADD score = 24.3, REVEL score = 0.783]. Based on the available evidence, the de novo heterozygous c.35G>A (p.Gly12Asp) variant identified inthe NRAS gene is reported as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Sep 22, 2024	- -

NRAS-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 13, 2022

The NRAS c.35G>A variant is predicted to result in the amino acid substitution p.Gly12Asp. This variant has been reported in individuals with Noonan syndrome and has been reported as a somatic variant in different types of cancers (van 't Veer et al. 1989. PubMed ID: 2674680; Matsuda et al. 2007. PubMed ID: 17332249; Mardis et al 2009. PubMed ID: 19657110; Hafner et al. 2012. PubMed ID: 22499344; MacConaill et al. 2014. PubMed ID: 25157968; Chang et al. 2015. PubMed ID: 26619011; Altmüller et al. 2017. PubMed ID: 28594414; Cifaldi et al. 2019. PubMed ID: 31031743). In ClinVar, this variant is interpreted as likely pathogenic and pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/39648/). This variant is reported in 0.0046% of alleles in individuals of European (Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-115258747-C-T). This variant is interpreted as pathogenic. -

Autoimmune lymphoproliferative syndrome type 4

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Lifecell International Pvt. Ltd

A Heterozygous Missense variant c.35G>A in Exon 2 of the NRAS gene that results in the amino acid substitution p.Gly12Asp was identified. The observed variant is novel in gnomAD exomes and genomes, respectively. The severity of the impact of this variant on the protein is medium, based on the effect of the protein and REVEL score. Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as Pathogenic/Likely Pathogenic [Variation ID: 39648]. The observed variation has been previously reported for primary melanoma of the CNS in children [Pedersen M, et.al, 2013]. Published functional studies suggests that the variant promotes oncogenesis/leukemogenesis [Wang et al., 2011]. For these reasons, this variant has been classified as Pathogenic. -

Epidermal nevus

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 05, 2013

- -

Juvenile myelomonocytic leukemia

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 05, 2013

- -

Cardiovascular phenotype

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 12, 2024

The p.G12D pathogenic mutation (also known as c.35G>A), located in coding exon 1 of the NRAS gene, results from a G to A substitution at nucleotide position 35. The glycine at codon 12 is replaced by aspartic acid, an amino acid with similar properties. This mutation has been detected in various types of cancers (van 't Veer LJ et al. Mol Cell Biol, 1989 Jul;9:3114-6; Vogelstein B et al. Genes Chromosomes Cancer, 1990 Jul;2:159-62; Brose MS et al. Cancer Res, 2002 Dec;62:6997-7000; Bacher U et al. Blood, 2006 May;107:3847-53; Matsuda K et al. Blood, 2007 Jun;109:5477-80; Vaughn CP et al. Genes Chromosomes Cancer, 2011 May;50:307-12). This variant has also been reported to be de novo in an individual with features consistent with Noonan syndrome (Altmüller F et al. Eur J Hum Genet, 2017 Jun;25:823-831). In addition, in vitro functional studies demonstrated that the mutation increases downstream Ras signaling (Tyner JW et al. Blood, 2009 Feb;113:1749-55). Embryonic expression of this mutation led to embryonic lethality and cardiac developmental defects (You X et al. Front Cell Dev Biol, 2021 Feb;9:633661). Endogenous expression of this variant at weaning induced myeloproliferative disorder, and mice that died of a spectrum of hematologic malignancies (Li Q et al. Blood, 2011 Feb;117:2022-32). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

RASopathy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 12, 2023

This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 12 of the NRAS protein (p.Gly12Asp). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with Noonan syndrome (PMID: 28594414). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 39648). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt NRAS protein function. This variant disrupts the p.Gly12 amino acid residue in NRAS. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 28098151, 28594414). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Noonan syndrome and Noonan-related syndrome

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Dec 01, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.39

BayesDel_noAF

Pathogenic

0.33

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.65

Eigen

Uncertain

0.65

Eigen_PC

Pathogenic

0.70

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.31

M_CAP

Uncertain

0.15

MetaRNN

Pathogenic

0.91

MetaSVM

Uncertain

0.16

MutationAssessor

Pathogenic

3.1

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.93

PROVEAN

Pathogenic

-5.3

REVEL

Pathogenic

0.78

Sift

Uncertain

0.011

Sift4G

Pathogenic

0.0

Polyphen

0.37

Vest4

0.91

MVP

0.93

MPC

2.0

ClinPred

0.99

GERP RS

5.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.9

Varity_R

0.89

gMVP

0.96

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