19-49635617-G-A

Position:

• chr19-49635617-G-A

Variant summary

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

The ENST00000246792.4(RRAS):​c.616C>T​(p.Pro206Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000078 in 1,281,662 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: 7.8e-7 (0 hom.)
• Consequence: RRAS ENST00000246792.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.41

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=0.21342754).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RRAS	NM_006270.5	c.616C>T	p.Pro206Ser	missense_variant	6/6	ENST00000246792.4	NP_006261.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RRAS	ENST00000246792.4	c.616C>T	p.Pro206Ser	missense_variant	6/6	1	NM_006270.5	ENSP00000246792	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 7.80e-7 AC: 1 AN: 1281662 Hom.: 0 Cov.: 31 AF XY: 0.00000160 AC XY: 1 AN XY: 625674

Gnomad4 AFR exome AF: 0.0000364

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 22, 2024

The p.P206S variant (also known as c.616C>T), located in coding exon 6 of the RRAS gene, results from a C to T substitution at nucleotide position 616. The proline at codon 206 is replaced by serine, an amino acid with similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.069	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.26	T
Eigen	Benign	0.025
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.76	T
M_CAP	Benign	0.045	D
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-0.81	T
MutationAssessor	Benign	0.24	N
MutationTaster	Benign	0.97	D
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	0.040	N
REVEL	Benign	0.064
Sift	Benign	0.25	T
Sift4G	Benign	0.24	T
Polyphen		0.69	P
Vest4		0.11
MutPred		0.29		Gain of phosphorylation at P206 (P = 0.0126);
MVP		0.84
MPC		0.67
ClinPred		0.40	T
GERP RS		4.9
Varity_R		0.077
gMVP		0.38

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs2080992338; hg19: chr19-50138874;