rs754976061

chr19-49640035-C-Achr19-49640035-C-Gchr19-49640035-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_006270.5(RRAS):c.64G>T(p.Gly22Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000361 in 1,383,790 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. G22G) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000036 (0 hom.)
• Consequence: RRAS NM_006270.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 0.756

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20776644).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RRAS	NM_006270.5	c.64G>T	p.Gly22Trp	missense_variant	1/6	ENST00000246792.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RRAS	ENST00000246792.4	c.64G>T	p.Gly22Trp	missense_variant	1/6	1	NM_006270.5	P1
RRAS	ENST00000601532.1	n.88G>T		non_coding_transcript_exon_variant	1/4	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000300 AC: 4 AN: 133342 Hom.: 0 AF XY: 0.0000396 AC XY: 3 AN XY: 75792

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000126

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000184

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000361 AC: 5 AN: 1383790 Hom.: 0 Cov.: 31 AF XY: 0.00000583 AC XY: 4 AN XY: 685530

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000112

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: 9.25e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000902 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Noonan syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	Nov 13, 2023	The RRAS c.64G>T (p.Gly22Trp) missense change has a maximum subpopulation frequency of 0.012% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a benign effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. To our knowledge, this variant has not been reported 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jun 29, 2022	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. 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 tolerated. ClinVar contains an entry for this variant (Variation ID: 527790). This variant has not been reported in the literature in individuals affected with RRAS-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces glycine, which is neutral and non-polar, with tryptophan, which is neutral and slightly polar, at codon 22 of the RRAS protein (p.Gly22Trp). -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Oct 01, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Benign	-0.084	T
BayesDel_noAF	Benign	-0.36
Cadd	Uncertain	24
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.47	T
Eigen	Benign	-0.091
Eigen_PC	Benign	-0.014
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.56	T
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	0.34	N
MutationTaster	Benign	0.95	N
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.11
Sift	Uncertain	0.015	D
Sift4G	Uncertain	0.0090	D
Polyphen		0.83	P
Vest4		0.27
MutPred		0.23		Loss of relative solvent accessibility (P = 0.0186);
MVP		0.78
MPC		0.52
ClinPred		0.15	T
GERP RS		2.4
Varity_R		0.068
gMVP		0.61

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

Publications

LitVar

Other links and lift over

dbSNP: rs754976061; hg19: chr19-50143292;