chr1-114716126-C-G

Variant names:

• chr1-114716126-C-G
• rs121913237
• NM_002524.5:c.35G>C

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_002524.5(NRAS):​c.35G>C​(p.Gly12Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,702 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. G12S) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: NRAS NM_002524.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 7.91
• Publications: 641 publications found

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 Gene-Disease associations (from GenCC):

• Noonan syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• Noonan syndrome 6

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia
• cardiofaciocutaneous syndrome

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Genomics England PanelApp, ClinGen
• Costello syndrome

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• Noonan syndrome with multiple lentigines

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 19 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 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 chr1-114716127-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 177778.Status of the report is reviewed_by_expert_panel, 3 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 30 curated pathogenic missense variants (we use a threshold of 10). The gene has 1 curated benign missense variants. Gene score misZ: 1.7139 (below the threshold of 3.09). Trascript score misZ: 2.2391 (below the threshold of 3.09). GenCC associations: The gene is linked to cardiofaciocutaneous syndrome, Noonan syndrome, Noonan syndrome 6, Costello syndrome, Noonan syndrome with multiple lentigines.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.965
• PP5: Variant 1-114716126-C-G is Pathogenic according to our data. Variant chr1-114716126-C-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 219097.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NRAS	NM_002524.5	c.35G>C	p.Gly12Ala	missense_variant	Exon 2 of 7	ENST00000369535.5	NP_002515.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NRAS	ENST00000369535.5	c.35G>C	p.Gly12Ala	missense_variant	Exon 2 of 7	1	NM_002524.5	ENSP00000358548.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461702 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727146

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111836

Other (OTH) AF: 0.00 AC: 0 AN: 60388

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autoimmune lymphoproliferative syndrome type 4 Pathogenic:1

Feb 11, 2025

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is observed at an extremely low frequency in the gnomAD v4.1.0 dataset (total allele frequency: <0.001%). Predicted Consequence/Location: Missense variant. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.69 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.98 (>=0.6, sensitivity 0.72 and precision 0.9)]. The same nucleotide change resulting in the same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000219097 /PMID: 32888943). Different missense changes at the same codon (p.Gly12Arg, p.Gly12Asp, p.Gly12Cys, p.Gly12Phe, p.Gly12Pro, p.Gly12Ser, p.Gly12Val) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000039648, VCV000040468, VCV000040469, VCV000040470, VCV000177778, VCV003029607 /PMID: 23334668, 28594414, 30417923 /3billion dataset). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

Colorectal cancer Pathogenic:1

Jan 01, 2023

Clinical Laboratory Sciences Program (CLSP), King Saud bin Abdulaziz University for Health Sciences (KSAU-HS)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM1, PM5, PP3, PM2, PP5

Myelodysplastic syndrome progressed to acute myeloid leukemia Pathogenic:1

Jan 08, 2016

Hospital of the University of Pennsylvania, Center for Personalized Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Activating mutation

Noonan syndrome 6 Pathogenic:1

Apr 14, 2025

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Pathogenic. Evidence in support of pathogenic classification: Variant is present in gnomAD <0.001 for a dominant condition (v4: 1 heterozygote(s), 0 homozygote(s)); This variant has moderate previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic or likely pathogenic by multiple clinical laboratories in ClinVar; Other missense variant(s) comparable to the one identified in this case have very strong previous evidence for pathogenicity. p.(Gly12Asp), p.(Gly12Ser), p.(Gly12Arg), p.(Gly12Cys), p.(Gly12Val) and p.(Gly12Phe) have all been classified as pathogenic or likely pathogenic by multiple clinical laboratories in ClinVar. Additional information: Variant is predicted to result in a missense amino acid change from glycine to alanine; This gene is associated with autosomal dominant disease; Alternative amino acid change(s) at the same position are present in gnomAD (Highest allele count: v4: 17 heterozygote(s), 0 homozygote(s)); Gain of function is a known mechanism of disease in this gene and is associated with NRAS-related conditions (OMIM); Variants in this gene are known to have variable expressivity. Noonan syndrome, caused by germline variants in the NRAS gene, have variable expressivity (PMID: 20301303).

not provided Pathogenic:1

Mar 29, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Identified in an individual with a likely primary immunodeficiency, however additional clinical information was not provided (PMID: 32888943); Not observed at significant frequency in large population cohorts (gnomAD); 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: 14522897, 24006859, 25886136, 28594414, 28098151, 32888943)

Noonan syndrome and Noonan-related syndrome Pathogenic:1

Aug 01, 2018

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

RASopathy Pathogenic:1

Nov 29, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. 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. 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. ClinVar contains an entry for this variant (Variation ID: 219097). This variant has not been reported in the literature in individuals affected with NRAS-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 12 of the NRAS protein (p.Gly12Ala).

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.63	D
Eigen	Pathogenic	0.69
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.076	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Uncertain	-0.045	T
MutationAssessor	Benign	1.5	L
PhyloP100		7.9
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-4.6	D
REVEL	Pathogenic	0.69
Sift	Benign	0.032	D
Sift4G	Uncertain	0.019	D
Vest4		0.82
ClinPred		0.99	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.9
Varity_R		0.86
gMVP		0.92
Mutation Taster		=2/98	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: rs121913237; hg19: chr1-115258747; COSMIC: COSV54736555; COSMIC: COSV54736555;