rs143020946

Positions:

• chr1-114709659-C-G
• chr1-114709659-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Strong

The NM_002524.5(NRAS):​c.360G>C​(p.Leu120Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. L120L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NRAS NM_002524.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.524

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a chain GTPase NRas (size 185) in uniprot entity RASN_HUMAN there are 14 pathogenic changes around while only 1 benign (93%) in NM_002524.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.972

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NRAS	NM_002524.5	c.360G>C	p.Leu120Phe	missense_variant	4/7	ENST00000369535.5	NP_002515.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NRAS	ENST00000369535.5	c.360G>C	p.Leu120Phe	missense_variant	4/7	1	NM_002524.5	ENSP00000358548	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.23
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.88	D
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.90	D
M_CAP	Uncertain	0.29	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Uncertain	0.053	D
MutationAssessor	Pathogenic	4.0	H
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-3.4	D
REVEL	Pathogenic	0.72
Sift	Uncertain	0.019	D
Sift4G	Pathogenic	0.0010	D
Polyphen		0.19	B
Vest4		0.75
MutPred		0.91		Loss of sheet (P = 0.0817);
MVP		0.97
MPC		1.0
ClinPred		0.99	D
GERP RS		3.6
Varity_R		0.71
gMVP		0.76

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-115252280;