rs988964363

Variant names:

• chr19-49635584-G-A
• rs988964363
• NM_006270.5:c.649C>T

Your query was ambiguous. Multiple possible variants found:

• chr19-49635584-G-A
• chr19-49635584-G-C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_006270.5(RRAS):​c.649C>T​(p.Leu217Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000775 in 1,290,926 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L217V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 7.7e-7 (0 hom.)
• Consequence: RRAS NM_006270.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.55
• 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: ClinGen, Genomics England PanelApp

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.29702824).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RRAS	NM_006270.5	c.649C>T	p.Leu217Phe	missense_variant	Exon 6 of 6	ENST00000246792.4	NP_006261.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RRAS	ENST00000246792.4	c.649C>T	p.Leu217Phe	missense_variant	Exon 6 of 6	1	NM_006270.5	ENSP00000246792.2
RRAS	ENST00000601532.1	n.*228C>T		downstream_gene_variant		5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 7.75e-7 AC: 1 AN: 1290926 Hom.: 0 Cov.: 30 AF XY: 0.00000159 AC XY: 1 AN XY: 629250

African (AFR) AF: 0.00 AC: 0 AN: 28072

American (AMR) AF: 0.00 AC: 0 AN: 24910

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18052

East Asian (EAS) AF: 0.00 AC: 0 AN: 34718

South Asian (SAS) AF: 0.00 AC: 0 AN: 58662

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47592

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4890

European-Non Finnish (NFE) AF: 9.79e-7 AC: 1 AN: 1021668

Other (OTH) AF: 0.00 AC: 0 AN: 52362

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	0.011	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.43	T
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.76	T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.30	T
MetaSVM	Benign	-0.49	T
MutationAssessor	Benign	1.5	L
PhyloP100		1.6
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.25
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.0050	D
Vest4		0.30
ClinPred		0.84	D
GERP RS		4.0
Varity_R		0.23
gMVP		0.61
Mutation Taster		=80/20	polymorphism

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

Other links and lift over

dbSNP: rs988964363; hg19: chr19-50138841;