rs760978291

Variant names:

• chr19-49635833-G-GAA
• rs760978291
• NM_006270.5:c.472_473insTT

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP6

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).

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., cov: 28)
  • Exomes 𝑓: 0.00029 (0 hom.)
• Consequence: RRAS NM_006270.5 frameshift
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 0.600

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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 id is 582390.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=2}.

Transcripts

RefSeq

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

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.000224 AC: 34 AN: 151622 Hom.: 0 Cov.: 28

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

GnomAD3 exomes AF: 0.000199 AC: 48 AN: 241452 Hom.: 0 AF XY: 0.000213 AC XY: 28 AN XY: 131604

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 SAS 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.: 0 Cov.: 29 AF XY: 0.000284 AC XY: 202 AN XY: 710198

Gnomad4 AFR exome AF: 0.0000304

Gnomad4 AMR exome AF: 0.0000228

Gnomad4 ASJ exome AF: 0.000156

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000193

Gnomad4 NFE exome AF: 0.000357

Gnomad4 OTH exome AF: 0.000256

GnomAD4 genome AF: 0.000224 AC: 34 AN: 151740 Hom.: 0 Cov.: 28 AF XY: 0.000175 AC XY: 13 AN XY: 74172

Gnomad4 AFR AF: 0.0000242

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000486

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000221 Hom.: 0

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Noonan syndrome Uncertain:2

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. -

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. -

not specified Benign:1

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

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs760978291; hg19: chr19-50139090;