1-114716127-C-G

Variant names:

• chr1-114716127-C-G
• rs121913250
• NM_002524.5:c.34G>C

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate PP5_Very_Strong

The NM_002524.5(NRAS):​c.34G>C​(p.Gly12Arg) 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. G12S) has been classified as Pathogenic. The gene NRAS is included in the ClinGen Criteria Specification Registry.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NRAS NM_002524.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 7.91
• Publications: 318 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: G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• cardiofaciocutaneous syndrome

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

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

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• Noonan syndrome-like disorder with loose anagen hair

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Specifications for NRAS are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Pathogenic. The variant received 17 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, 5 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 Noonan syndrome with multiple lentigines, Noonan syndrome 6, cardiofaciocutaneous syndrome, Noonan syndrome-like disorder with loose anagen hair, Noonan syndrome, Costello syndrome.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.938
• PP5: Variant 1-114716127-C-G is Pathogenic according to our data. Variant chr1-114716127-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 40469.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002524.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NRAS	NM_002524.5	MANE Select	c.34G>C	p.Gly12Arg	missense	Exon 2 of 7	NP_002515.1	Q5U091

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NRAS	ENST00000369535.5	TSL:1 MANE Select	c.34G>C	p.Gly12Arg	missense	Exon 2 of 7	ENSP00000358548.4	P01111
	NRAS	ENST00000899430.1		c.34G>C	p.Gly12Arg	missense	Exon 2 of 8	ENSP00000569489.1
	NRAS	ENST00000931010.1		c.34G>C	p.Gly12Arg	missense	Exon 2 of 7	ENSP00000601069.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
4	-	-	Noonan syndrome 6 (4)
1	-	-	Increased nuchal translucency (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.27
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.66	D
Eigen	Uncertain	0.63
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.071	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Uncertain	-0.081	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		7.9
PrimateAI	Pathogenic	0.93	D
PROVEAN	Pathogenic	-6.1	D
REVEL	Pathogenic	0.71
Sift	Uncertain	0.021	D
Sift4G	Uncertain	0.0050	D
Polyphen		0.61	P
Vest4		0.91
MutPred		0.82		Gain of MoRF binding (P = 0.0105)
MVP		0.91
MPC		2.2
ClinPred		1.0	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.9
Varity_R		0.85
gMVP		0.95
Mutation Taster		=9/91	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: rs121913250; hg19: chr1-115258748; COSMIC: COSV54736940; COSMIC: COSV54736940;