19-49635623-T-C

Variant summary

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

The NM_006270.5(RRAS):c.610A>G(p.Ser204Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000171 in 1,284,254 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.000017 (0 hom.)
• Consequence: RRAS NM_006270.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.871

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=0.119113624).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RRAS	NM_006270.5	c.610A>G	p.Ser204Gly	missense_variant	6/6	ENST00000246792.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RRAS	ENST00000246792.4	c.610A>G	p.Ser204Gly	missense_variant	6/6	1	NM_006270.5	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000641 AC: 1 AN: 156118 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 83298

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.0000127

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000171 AC: 22 AN: 1284254 Hom.: 0 Cov.: 31 AF XY: 0.0000159 AC XY: 10 AN XY: 627138

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: 0.0000217

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ExAC AF: 0.00000827 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Noonan syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 05, 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. This variant has not been reported in the literature in individuals affected with RRAS-related conditions. This variant is present in population databases (rs546673930, gnomAD 0.001%). This sequence change replaces serine, which is neutral and polar, with glycine, which is neutral and non-polar, at codon 204 of the RRAS protein (p.Ser204Gly). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
Cadd	Benign	20
Dann	Uncertain	0.99
DEOGEN2	Benign	0.25	T
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.28
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.45	T
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.49	N
MutationTaster	Benign	1.0	N
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.50	N
REVEL	Benign	0.13
Sift	Benign	0.17	T
Sift4G	Benign	0.31	T
Polyphen		0.039	B
Vest4		0.064
MutPred		0.27		Loss of phosphorylation at S204 (P = 0.0078);
MVP		0.80
MPC		0.41
ClinPred		0.072	T
GERP RS		4.9
Varity_R		0.071
gMVP		0.42

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs546673930; hg19: chr19-50138880;