chr1-114713941-G-A

Variant names:

• chr1-114713941-G-A
• rs267606921
• NM_002524.5:c.149C>T

Variant summary

Our verdict is Pathogenic. The variant received 9 ACMG points: 9P and 0B. PM2_Supporting PS3_Moderate PS4 PM6

This summary comes from the ClinGen Evidence Repository: The c.149C>T (p.Thr50Ile) variant in NRAS is a missense variant predicted to cause substitution of threonine by isoleucine at amino acid 50. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.693, which is neither above nor below the thresholds predicting a damaging or benign impact on NRAS function. This variant has been reported in over 6 probands with features of RASopathy (PS4; PMIDs: 22855653, 28594414, 31219622, GeneDx). This variant has been identified as a de novo occurrence with unconfirmed parental relationships in 4 individuals with autosomal dominant RASopathy (PM6_VeryStrong; PMIDs: 19966803, 29752777, APHP-Robert Debré). MEK and ERK activation assays in COS-7 cells showed enhanced phosphorylation of MEK and ERK in the presence of serum or after EGF stimulation indicating that this variant impacts protein function (PMID:19966803)(PS3_Moderate). In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant RASopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy VCEP: PM6_VeryStrong, PS4, PS3_Moderate, PM2_Supporting. (RASopathy VCEP specifications version 2.1; 9/17/2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA257019/MONDO:0021060/039

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.3e-7 (0 hom.)
• Consequence: NRAS NM_002524.5 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:7 O:1
• Conservation: PhyloP100: 9.87
• Publications: 36 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 9 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM6: For more information check the summary or visit ClinGen Evidence Repository.

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.149C>T	p.Thr50Ile	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.149C>T	p.Thr50Ile	missense	Exon 3 of 7	ENSP00000358548.4	P01111
	NRAS	ENST00000899430.1		c.149C>T	p.Thr50Ile	missense	Exon 3 of 8	ENSP00000569489.1
	NRAS	ENST00000931010.1		c.149C>T	p.Thr50Ile	missense	Exon 3 of 7	ENSP00000601069.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.33e-7 AC: 1 AN: 1364650 Hom.: 0 Cov.: 31 AF XY: 0.00000148 AC XY: 1 AN XY: 676466

⚠️ 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: 30718

American (AMR) AF: 0.00 AC: 0 AN: 41644

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22826

East Asian (EAS) AF: 0.00 AC: 0 AN: 33106

South Asian (SAS) AF: 0.00 AC: 0 AN: 84926

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 44208

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5300

European-Non Finnish (NFE) AF: 9.54e-7 AC: 1 AN: 1047906

Other (OTH) AF: 0.00 AC: 0 AN: 54016

⚠️ 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

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
3	-	-	Noonan syndrome 6 (3)
3	-	-	RASopathy (3)
1	-	-	Noonan syndrome (1)
-	-	-	Noonan syndrome 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.50
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.63	D
Eigen	Benign	0.073
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.019	T
MetaRNN	Pathogenic	0.86	D
MetaSVM	Benign	-0.74	T
MutationAssessor	Benign	0.67	N
PhyloP100		9.9
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-3.7	D
REVEL	Pathogenic	0.69
Sift	Benign	0.054	T
Sift4G	Benign	0.22	T
Polyphen		0.18	B
Vest4		0.90
MutPred		0.78		Loss of sheet (P = 0.1158)
MVP		0.96
MPC		2.1
ClinPred		0.97	D
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.83
gMVP		0.65
Mutation Taster		=15/85	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs267606921; hg19: chr1-115256562; COSMIC: COSV54755793; COSMIC: COSV54755793;