rs373359206

Variant names:

• chr19-49640050-C-A
• rs373359206
• NM_006270.5:c.49G>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_006270.5(RRAS):​c.49G>T​(p.Gly17Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000374 in 1,497,646 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G17V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00024 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: RRAS NM_006270.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 0.567
• 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: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.04683566).
• BP6: Variant 19-49640050-C-A is Benign according to our data. Variant chr19-49640050-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 575657.
• BS2: High AC in GnomAd4 at 37 AD gene.

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.49G>T	p.Gly17Trp	missense	Exon 1 of 6	NP_006261.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RRAS	ENST00000246792.4	TSL:1 MANE Select	c.49G>T	p.Gly17Trp	missense	Exon 1 of 6	ENSP00000246792.2
	RRAS	ENST00000962270.1		c.49G>T	p.Gly17Trp	missense	Exon 1 of 7	ENSP00000632329.1
	RRAS	ENST00000928399.1		c.49G>T	p.Gly17Trp	missense	Exon 1 of 6	ENSP00000598458.1

Frequencies

GnomAD3 genomes AF: 0.000243 AC: 37 AN: 151990 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000845

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000543 AC: 5 AN: 92070 AF XY: 0.0000188

Gnomad AFR exome AF: 0.00144

Gnomad AMR exome AF: 0.0000597

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000141 AC: 19 AN: 1345656 Hom.: 0 Cov.: 31 AF XY: 0.0000120 AC XY: 8 AN XY: 664874

African (AFR) AF: 0.000509 AC: 14 AN: 27488

American (AMR) AF: 0.0000352 AC: 1 AN: 28386

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22822

East Asian (EAS) AF: 0.00 AC: 0 AN: 32178

South Asian (SAS) AF: 0.00 AC: 0 AN: 76106

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34714

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4008

European-Non Finnish (NFE) AF: 0.00000188 AC: 2 AN: 1064216

Other (OTH) AF: 0.0000359 AC: 2 AN: 55738

GnomAD4 genome AF: 0.000243 AC: 37 AN: 151990 Hom.: 0 Cov.: 32 AF XY: 0.000175 AC XY: 13 AN XY: 74240

African (AFR) AF: 0.000845 AC: 35 AN: 41408

American (AMR) AF: 0.0000655 AC: 1 AN: 15272

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5136

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67950

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.000142 Hom.: 0

Bravo AF: 0.000200

ExAC AF: 0.0000753 AC: 7

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not specified (2)
-	1	-	Noonan syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.21
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.47	T
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Benign	0.59	D
LIST_S2	Benign	0.57	T
M_CAP	Pathogenic	0.55	D
MetaRNN	Benign	0.047	T
MetaSVM	Uncertain	-0.23	T
MutationAssessor	Benign	0.34	N
PhyloP100		0.57
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-1.1	N
REVEL	Uncertain	0.29
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.36
MutPred		0.23		Loss of relative solvent accessibility (P = 0.0186)
MVP		0.79
MPC		1.4
ClinPred		0.16	T
GERP RS		4.6
PromoterAI		0.028	Neutral
Varity_R		0.19
gMVP		0.63
Mutation Taster		=85/15	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: rs373359206; hg19: chr19-50143307;