chr1-114716123-C-T

Position:

chr1-114716123-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The ENST00000369535.5(NRAS):c.38G>A(p.Gly13Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,732 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G13A) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

NRAS
ENST00000369535.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 7.91

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 4 uncertain in ENST00000369535.5

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-114716124-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 13899.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.984

PP5

Variant 1-114716123-C-T is Pathogenic according to our data. Variant chr1-114716123-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 13901.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NRAS	NM_002524.5 linkuse as main transcript	c.38G>A	p.Gly13Asp	missense_variant	2/7	ENST00000369535.5	NP_002515.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NRAS	ENST00000369535.5 linkuse as main transcript	c.38G>A	p.Gly13Asp	missense_variant	2/7	1	NM_002524.5	ENSP00000358548	P1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251492

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135920

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461732

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727160

show subpopulations

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:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.000106

Hom.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Autoimmune lymphoproliferative syndrome type 4

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Diagnostic Genetics, Severance Hospital, Yonsei University College of Medicine	Jan 03, 2023	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 10, 2011	- -

Noonan syndrome 6

Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 10, 2011	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Oct 10, 2024	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0101 - Gain of function is a known mechanism of disease in this gene and is associated with NRAS-related conditions (OMIM). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Noonan syndrome, caused by germline variants in the NRAS gene, have variable expressivity (GeneReviews). (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to aspartic acid. (I) 0254 - This variant is low level mosaic in DNA extracted from snap frozen skin biopsy. (I) 0302 - Variant is present in gnomAD <0.001 for a dominant condition (v2: 1 heterozygote, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2: 1 heterozygote, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants (DECIPHER). (SP) 0801 - This variant has very strong previous evidence of pathogenicity in unrelated individuals. It is one of the variants in this gene most commonly associated with juvenile myelomonocytic leukaemia (JMML) and it has also been reported in somatic tissue associated with other cancers (ClinVar, PMIDs: 17332249, 18375819, 36130886). In addition, it has been regarded as pathogenic in germline tissue (ClinVar) and has been reported de novo in one individual with JMML and features of Noonan syndrome (PMID: 19775298) and in another individual with autoimmune lymphoproliferative syndrome without features of Noonan syndrome (PMID: 17517660). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

not provided

Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Jan 15, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 30, 2015	The G13D variant has been reported as a de novo germline variant in association with autoimmune lymphoproliferative syndrome (ALPS) (Oliveira et al., 2007). In vitro functional studies demonstrated that the presence of the G13D variant resulted in BCL-2-interacting mediator of cell death down-regulation and defective intrinsic mitochondrial apoptosis prominently in lymphocytes, leading to features of ALPS and hematopoietic malignancies (Oliveira et al., 2007). The G13D variant has also been reported as a germline variant in association with dysmorphic features and Juvenile Myelomonocytic Leukemia (JMML) (De Filippi et al., 2009). The G13D variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. -

Juvenile myelomonocytic leukemia

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 10, 2011

- -

Acute megakaryoblastic leukemia in down syndrome

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Sep 01, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.37

BayesDel_noAF

Pathogenic

0.29

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.75

Eigen

Uncertain

0.65

Eigen_PC

Pathogenic

0.70

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.86

M_CAP

Benign

0.055

MetaRNN

Pathogenic

0.98

MetaSVM

Uncertain

-0.083

MutationAssessor

Pathogenic

3.3

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.93

PROVEAN

Pathogenic

-5.5

REVEL

Pathogenic

0.70

Sift

Uncertain

0.029

Sift4G

Uncertain

0.023

Polyphen

0.43

Vest4

0.98

MutPred

0.97

Loss of catalytic residue at V14 (P = 0.1046);

MVP

0.92

MPC

1.2

ClinPred

0.97

GERP RS

5.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.9

Varity_R

0.89

gMVP

0.92

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over