1-114713941-G-A

Position:

• chr1-114713941-G-A

Variant summary

Our verdict is Pathogenic. Variant got 9 ACMG points: 9P and 0B. PM6 PM2_Supporting PS3_Moderate PS4

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:6 O:1
• Conservation: PhyloP100: 9.87

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 Pathogenic. Variant got 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NRAS	NM_002524.5	c.149C>T	p.Thr50Ile	missense_variant	3/7	ENST00000369535.5	NP_002515.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NRAS	ENST00000369535.5	c.149C>T	p.Thr50Ile	missense_variant	3/7	1	NM_002524.5	ENSP00000358548.4

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.54e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

RASopathy Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 11, 2022	Variant summary: NRAS c.149C>T (p.Thr50Ile) results in a non-conservative amino acid change located in the Small GTP-binding protein domain (IPR005225) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 251196 control chromosomes (gnomAD). c.149C>T has been reported in the literature in individuals affected with Noonan Syndrome and Related Conditions (Cirstea_2010, Denayer_2012, Altmuller_2017, Rodriguez_2018, Li_2019), including at least one confirmed de novo occurrence (Rodriguez_2018). These data indicate that the variant is very likely to be associated with disease. In zebrafish embryos the variant resulted in severe developmental defects during epiboly and gastrulation that resembled the defects observed with known Noonan-associated genes (Runtuwene_2011). Three ClinVar submitters have assessed the variant since 2014: all three classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 17, 2022	This variant is not present in population databases (gnomAD no frequency). This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 50 of the NRAS protein (p.Thr50Ile). This missense change has been observed in individual(s) with Noonan Syndrome (PMID: 19966803, 22855653). In at least one individual the variant was observed to be de novo. For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects NRAS function (PMID: 19966803, 21263000). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 13902). -
Pathogenic, reviewed by expert panel	curation	ClinGen RASopathy Variant Curation Expert Panel	Sep 17, 2024	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) -

Noonan syndrome 6 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Juno Genomics, Hangzhou Juno Genomics, Inc	-	PM2_Supporting+PS4+PM6_Strong+PP4+PS3_Moderate -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2010	- -

Noonan syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 06, 2013

The Thr50Ile variant has been reported in 2 individuals with clinical features o f Noonan syndrome (Cirstea 2010). This variant was reported to have occurred de novo in these individuals. Studies have shown that the Thr50Ile variant may impa ct protein function (Cirstea 2010, Runtuwene 2011). However, this in vitro assay may not accurately represent biological function. Computational analyses (bioch emical amino acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) also suggest that the Thr50Ile variant may impact the protein, though this informati on is not predictive enough to determine pathogenicity. In summary, this varian t meets our criteria to be classified as pathogenic (http://pcpgm.partners.org/L MM). -

Noonan syndrome 1 Other:1

not provided, no classification provided

literature only

GeneReviews

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Computational scores

Source: dbNSFP v4.3

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
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

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

Publications

LitVar

Other links and lift over

dbSNP: rs267606921; hg19: chr1-115256562; COSMIC: COSV54755793; COSMIC: COSV54755793;