chr1-114709659-C-T

Variant names:

• chr1-114709659-C-T
• rs143020946
• NM_002524.5:c.360G>A

Variant summary

Our verdict is Likely benign. The variant received -7 ACMG points: 0P and 7B. BP4 BP5 BP7 BS1

This summary comes from the ClinGen Evidence Repository: The NM_002524.5:c.360G>A (p.Leu120=) variant is a synonymous (silent) variant in NRAS that is not predicted by SpliceAI to impact splicing. In addition, it occurs at a nucleotide that is not conserved as shown by UCSC Genome Browser (BP4, BP7). The filtering allele frequency (the lower threshold of the 95% CI of 77/129188) of the c.360G>A variant in NRAS is 0.0004832 for European (non-Finnish) chromosomes by gnomAD v2.1.1, which is higher than the ClinGen RASopathy VCEP threshold (≥0.00025) for BS1, and therefore meets this criterion (BS1). Observed in 1 individual with a co-occurring likely pathogenic/pathogenic variant in a gene that explains their condition, Noonan syndrome (Invitae internal data, ClinVar SCV000253394.6). In summary, this variant meets the criteria to be classified as likely benign for autosomal dominant RASopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy VCEP: BS1, BP4, BP5, BP7. (ClinGen RASopathy VCEP specifications version 2.3; 12/3/2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA134569/MONDO:0021060/039

• Frequency:
  • Genomes: 𝑓 0.00033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00056 (0 hom.)
• Consequence: NRAS NM_002524.5 synonymous
• Clinical Significance: Likely benign reviewed by expert panel U:1 B:11
• Conservation: PhyloP100: 0.524
• Publications: 7 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: Likely_benign. The variant received -7 ACMG points.

• BP4: For more information check the summary or visit ClinGen Evidence Repository.
• BP5: For more information check the summary or visit ClinGen Evidence Repository.
• BP7: For more information check the summary or visit ClinGen Evidence Repository.
• BS1: 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.360G>A	p.Leu120Leu	synonymous	Exon 4 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.360G>A	p.Leu120Leu	synonymous	Exon 4 of 7	ENSP00000358548.4	P01111
	NRAS	ENST00000899430.1		c.417G>A	p.Leu139Leu	synonymous	Exon 5 of 8	ENSP00000569489.1
	NRAS	ENST00000931010.1		c.360G>A	p.Leu120Leu	synonymous	Exon 4 of 7	ENSP00000601069.1

Frequencies

GnomAD3 genomes AF: 0.000329 AC: 50 AN: 152120 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000588

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000314 AC: 79 AN: 251484 AF XY: 0.000346

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000598

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000557 AC: 814 AN: 1461028 Hom.: 0 Cov.: 30 AF XY: 0.000539 AC XY: 392 AN XY: 726878

African (AFR) AF: 0.0000299 AC: 1 AN: 33458

American (AMR) AF: 0.000201 AC: 9 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86240

European-Finnish (FIN) AF: 0.0000374 AC: 2 AN: 53420

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5764

European-Non Finnish (NFE) AF: 0.000689 AC: 766 AN: 1111236

Other (OTH) AF: 0.000530 AC: 32 AN: 60356

GnomAD4 genome AF: 0.000328 AC: 50 AN: 152238 Hom.: 0 Cov.: 32 AF XY: 0.000309 AC XY: 23 AN XY: 74444

African (AFR) AF: 0.000144 AC: 6 AN: 41536

American (AMR) AF: 0.000262 AC: 4 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000588 AC: 40 AN: 68016

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000488 Hom.: 0

Bravo AF: 0.000363

EpiCase AF: 0.000600

EpiControl AF: 0.000593

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	3	not specified (3)
-	-	2	RASopathy (2)
-	-	1	Cardiovascular phenotype (1)
-	1	-	Noonan syndrome 6 (1)
-	-	1	Noonan syndrome and Noonan-related syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.34
CADD	Benign	10
DANN	Benign	0.75
PhyloP100		0.52
Mutation Taster		=96/4	polymorphism

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: rs143020946; hg19: chr1-115252280; COSMIC: COSV65742305;