NM_006270.5:c.645C>T

Variant names:

• chr19-49635588-G-A
• rs149038492
• NM_006270.5:c.645C>T

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_Moderate BP6_Very_Strong BP7 BS2

The NM_006270.5(RRAS):​c.645C>T​(p.Cys215Cys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000132 in 1,444,220 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: RRAS NM_006270.5 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.0220
• 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: Benign. The variant received -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 19-49635588-G-A is Benign according to our data. Variant chr19-49635588-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 1665914.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.022 with no splicing effect.
• BS2: High AC in GnomAd4 at 6 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.645C>T	p.Cys215Cys	synonymous	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.645C>T	p.Cys215Cys	synonymous	Exon 6 of 6	ENSP00000246792.2	P10301
	RRAS	ENST00000962270.1		c.684C>T	p.Cys228Cys	synonymous	Exon 7 of 7	ENSP00000632329.1
	RRAS	ENST00000928399.1		c.654C>T	p.Cys218Cys	synonymous	Exon 6 of 6	ENSP00000598458.1

Frequencies

GnomAD3 genomes AF: 0.0000395 AC: 6 AN: 152038 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000725

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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: 0.0000515 AC: 8 AN: 155208 AF XY: 0.0000244

Gnomad AFR exome AF: 0.0000749

Gnomad AMR exome AF: 0.000430

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: 0.0000101 AC: 13 AN: 1292182 Hom.: 0 Cov.: 30 AF XY: 0.00000952 AC XY: 6 AN XY: 630146

African (AFR) AF: 0.0000356 AC: 1 AN: 28092

American (AMR) AF: 0.000320 AC: 8 AN: 25012

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18076

East Asian (EAS) AF: 0.00 AC: 0 AN: 34772

South Asian (SAS) AF: 0.0000169 AC: 1 AN: 59078

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47652

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4898

European-Non Finnish (NFE) AF: 9.78e-7 AC: 1 AN: 1022184

Other (OTH) AF: 0.0000382 AC: 2 AN: 52418

GnomAD4 genome AF: 0.0000395 AC: 6 AN: 152038 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 74254

African (AFR) AF: 0.0000725 AC: 3 AN: 41386

American (AMR) AF: 0.000131 AC: 2 AN: 15262

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68002

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.0000658 Hom.: 0

Bravo AF: 0.000106

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Noonan syndrome (1)
-	-	1	not specified (1)
-	-	1	RRAS-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	7.8
DANN	Benign	0.59
PhyloP100		-0.022

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs149038492; hg19: chr19-50138845;