1-114713908-T-C

Variant names:

• chr1-114713908-T-C
• rs11554290
• NM_002524.5:c.182A>G

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.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 Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NRAS NM_002524.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:13 O:7
• Conservation: PhyloP100: 7.91
• Publications: 2149 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

Our verdict: Pathogenic. The variant received 17 ACMG points.

• PM1: In a hotspot region, there are 8 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 chr1-114713908-T-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 375874.
• 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, 0.876
• PP5: Variant 1-114713908-T-C is Pathogenic according to our data. Variant chr1-114713908-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 13900.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.182A>G	p.Gln61Arg	missense	Exon 3 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.182A>G	p.Gln61Arg	missense	Exon 3 of 7	ENSP00000358548.4	P01111
	NRAS	ENST00000899430.1		c.182A>G	p.Gln61Arg	missense	Exon 3 of 8	ENSP00000569489.1
	NRAS	ENST00000931010.1		c.182A>G	p.Gln61Arg	missense	Exon 3 of 7	ENSP00000601069.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.000198 Hom.: 1

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
4	-	-	not provided (4)
1	-	-	Colorectal cancer (1)
1	-	-	Epidermal nevus (1)
1	-	-	Large congenital melanocytic nevus (1)
1	-	-	Linear nevus sebaceous syndrome (1)
1	-	-	Neurocutaneous melanocytosis (1)
1	-	-	Non-small cell lung carcinoma (1)
1	-	-	Noonan syndrome 6 (1)
1	-	-	Thyroid cancer, nonmedullary, 2 (1)
1	-	-	Vascular malformation (1)
-	-	-	Diffuse midline glioma, H3 K27M-mutant (1)
-	-	-	Embryonal rhabdomyosarcoma (1)
-	-	-	Follicular thyroid carcinoma (1)
-	-	-	Germinoma (1)
-	-	-	Melanoma (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.69	D
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.88	D
MetaSVM	Uncertain	0.29	D
MutationAssessor	Pathogenic	3.3	M
PhyloP100		7.9
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-3.4	D
REVEL	Pathogenic	0.89
Sift	Uncertain	0.029	D
Sift4G	Uncertain	0.048	D
Polyphen		0.21	B
Vest4		0.80
MutPred		0.75		Loss of glycosylation at T58 (P = 0.1035)
MVP		0.97
MPC		0.99
ClinPred		0.98	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.84
gMVP		0.83
Mutation Taster		=7/93	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: rs11554290; hg19: chr1-115256529; COSMIC: COSV54736340; COSMIC: COSV54736340;