rs2080992427

Variant names:

• chr19-49635628-G-A
• rs2080992427
• NM_006270.5:c.605C>T

Your query was ambiguous. Multiple possible variants found:

• chr19-49635628-G-A
• chr19-49635628-G-C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_006270.5(RRAS):​c.605C>T​(p.Pro202Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,130 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: RRAS NM_006270.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.14
• Publications: 0 publications found

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: Genomics England PanelApp, PanelApp Australia, ClinGen
• cardiofaciocutaneous syndrome

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• Costello syndrome

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• Noonan syndrome with multiple lentigines

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• Noonan syndrome-like disorder with loose anagen hair

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18335181).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006270.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RRAS	NM_006270.5	MANE Select	c.605C>T	p.Pro202Leu	missense	Exon 6 of 6	NP_006261.1	P10301

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RRAS	ENST00000246792.4	TSL:1 MANE Select	c.605C>T	p.Pro202Leu	missense	Exon 6 of 6	ENSP00000246792.2	P10301
	RRAS	ENST00000962270.1		c.644C>T	p.Pro215Leu	missense	Exon 7 of 7	ENSP00000632329.1
	RRAS	ENST00000928399.1		c.614C>T	p.Pro205Leu	missense	Exon 6 of 6	ENSP00000598458.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152130 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

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: 0.00

Gnomad OTH AF: 0.000478

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1288724 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 629702

African (AFR) AF: 0.00 AC: 0 AN: 27718

American (AMR) AF: 0.00 AC: 0 AN: 26082

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18298

East Asian (EAS) AF: 0.00 AC: 0 AN: 33720

South Asian (SAS) AF: 0.00 AC: 0 AN: 60734

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47424

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4946

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1017870

Other (OTH) AF: 0.00 AC: 0 AN: 51932

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152130 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 74308

African (AFR) AF: 0.00 AC: 0 AN: 41436

American (AMR) AF: 0.00 AC: 0 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4808

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68016

Other (OTH) AF: 0.000478 AC: 1 AN: 2094

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.38	T
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.31
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.75	T
M_CAP	Benign	0.046	D
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		2.1
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.051
Sift	Benign	0.032	D
Sift4G	Benign	0.083	T
Polyphen		0.0060	B
Vest4		0.22
MutPred		0.28		Loss of glycosylation at P202 (P = 0.0041)
MVP		0.73
MPC		0.46
ClinPred		0.24	T
GERP RS		3.9
Varity_R		0.070
gMVP		0.42
Mutation Taster		=81/19	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs2080992427; hg19: chr19-50138885;