rs760978291

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP6BS2

The NM_006270.5(RRAS):c.472_473insTT(p.Ser158PhefsTer77) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000281 in 1,583,240 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.00022 ( 0 hom., cov: 28)

Exomes 𝑓: 0.00029 ( 0 hom. )

Consequence

RRAS
NM_006270.5 frameshift

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:2

Conservation

PhyloP100: 0.600

Publications

0 publications found

Variant links:

Genes affected

RRAS (HGNC:10447): (RAS related) The protein encoded by this gene is a small GTPase involved in diverse processes including angiogenesis, vascular homeostasis and regeneration, cell adhesion, and neuronal axon guidance. Mutations in this gene are found in many invasive cancers. [provided by RefSeq, Jul 2015]

RRAS Gene-Disease associations (from GenCC):

Noonan syndrome and Noonan-related syndrome
Inheritance: AD Classification: STRONG Submitted by: G2P
Noonan syndrome
Inheritance: AD Classification: MODERATE, LIMITED Submitted by: ClinGen, Genomics England PanelApp

RRAS links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP6

Variant 19-49635833-G-GAA is Benign according to our data. Variant chr19-49635833-G-GAA is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 582390.

BS2

High AC in GnomAd4 at 34 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RRAS	NM_006270.5 link	c.472_473insTT	p.Ser158PhefsTer77	frameshift_variant	Exon 5 of 6	ENST00000246792.4	NP_006261.1	P10301A0A024QZF2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RRAS	ENST00000246792.4 link	c.472_473insTT	p.Ser158PhefsTer77	frameshift_variant	Exon 5 of 6	1	NM_006270.5	ENSP00000246792.2		P10301
RRAS	ENST00000601532.1 link	n.612_613insTT		non_coding_transcript_exon_variant	Exon 4 of 4	5

Frequencies

GnomAD3 genomes

AF:

0.000224

AC:

AN:

151622

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.000486

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000199

AC:

AN:

241452

AF XY:

0.000213

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000299

Gnomad ASJ exome

AF:

0.000102

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000424

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000287

AC:

411

AN:

1431500

Hom.:

Cov.:

AF XY:

0.000284

AC XY:

202

AN XY:

710198

show subpopulations

African (AFR)

AF:

0.0000304

AC:

AN:

32848

American (AMR)

AF:

0.0000228

AC:

AN:

43946

Ashkenazi Jewish (ASJ)

AF:

0.000156

AC:

AN:

25578

East Asian (EAS)

AF:

0.00

AC:

AN:

38804

South Asian (SAS)

AF:

0.00

AC:

AN:

84872

European-Finnish (FIN)

AF:

0.0000193

AC:

AN:

51870

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5564

European-Non Finnish (NFE)

AF:

0.000357

AC:

389

AN:

1089374

Other (OTH)

AF:

0.000256

AC:

AN:

58644

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000224

AC:

AN:

151740

Hom.:

Cov.:

AF XY:

0.000175

AC XY:

AN XY:

74172

show subpopulations

African (AFR)

AF:

0.0000242

AC:

AN:

41378

American (AMR)

AF:

0.00

AC:

AN:

15262

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3464

East Asian (EAS)

AF:

0.00

AC:

AN:

5164

South Asian (SAS)

AF:

0.00

AC:

AN:

4772

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10532

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000486

AC:

AN:

67866

Other (OTH)

AF:

0.00

AC:

AN:

2098

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000221

Hom.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Noonan syndrome

Uncertain:2

Oct 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change creates a premature translational stop signal (p.Ser158Phefs*77) in the RRAS gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 61 amino acid(s) of the RRAS protein. This variant is present in population databases (rs760978291, gnomAD 0.05%), and has an allele count higher than expected for a pathogenic variant. This premature translational stop signal has been observed in individual(s) with Noonan (internal data). ClinVar contains an entry for this variant (Variation ID: 582390). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Dec 10, 2024

St. Jude Molecular Pathology, St. Jude Children's Research Hospital

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The RRAS c.472_473insTT (p.Ser158PhefsTer77) change inserts two nucleotides to cause a frameshift. This variant occurs at the 3' terminus of the RRAS gene and is expected to result in the elongation of the native protein by replacing the last 61 amino acids with 76 different amino acids. To our knowledge, this variant has not been reported in the literature in individuals with Noonan syndrome. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance. -

not specified

Benign:2

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 09, 2020

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: RRAS c.472_473insTT (p.Ser158PhefsX77) causes a frameshift which results in an extension of the protein. The variant allele was found at a frequency of 0.0002 in 241452 control chromosomes, predominantly at a frequency of 0.00042 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 168 fold of the estimated maximal expected allele frequency for a pathogenic variant in RRAS causing Noonan Syndrome And Related Conditions phenotype (2.5e-06), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. To our knowledge, no occurrence of c.472_473insTT in individuals affected with Noonan Syndrome And Related Conditions and no experimental evidence demonstrating its impact on protein function have been reported. One ClinVar submitter (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.60

Mutation Taster

=32/168

disease causing

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over