chr19-49636693-G-A

Variant names:

• chr19-49636693-G-A
• rs145907892
• NM_006270.5:c.379C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Moderate BP6_Very_Strong BS2

The NM_006270.5(RRAS):​c.379C>T​(p.Leu127Leu) variant causes a synonymous change. The variant allele was found at a frequency of 0.00144 in 1,614,158 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0015 (2 hom.)
• Consequence: RRAS NM_006270.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 4.99
• 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 19-49636693-G-A is Benign according to our data. Variant chr19-49636693-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 457986.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 164 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.379C>T	p.Leu127Leu	synonymous	Exon 4 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.379C>T	p.Leu127Leu	synonymous	Exon 4 of 6	ENSP00000246792.2	P10301
	RRAS	ENST00000962270.1		c.418C>T	p.Leu140Leu	synonymous	Exon 5 of 7	ENSP00000632329.1
	RRAS	ENST00000928399.1		c.388C>T	p.Leu130Leu	synonymous	Exon 4 of 6	ENSP00000598458.1

Frequencies

GnomAD3 genomes AF: 0.00108 AC: 164 AN: 152208 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.0121

Gnomad AMR AF: 0.00131

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: 0.00173

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.000896 AC: 225 AN: 251146 AF XY: 0.000899

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000926

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.00154

Gnomad OTH exome AF: 0.000652

GnomAD4 exome AF: 0.00148 AC: 2160 AN: 1461832 Hom.: 2 Cov.: 32 AF XY: 0.00137 AC XY: 994 AN XY: 727212

African (AFR) AF: 0.000179 AC: 6 AN: 33480

American (AMR) AF: 0.00105 AC: 47 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000301 AC: 26 AN: 86258

European-Finnish (FIN) AF: 0.0000562 AC: 3 AN: 53410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00176 AC: 1958 AN: 1111970

Other (OTH) AF: 0.00197 AC: 119 AN: 60386

GnomAD4 genome AF: 0.00108 AC: 164 AN: 152326 Hom.: 0 Cov.: 31 AF XY: 0.000859 AC XY: 64 AN XY: 74490

African (AFR) AF: 0.000313 AC: 13 AN: 41574

American (AMR) AF: 0.00131 AC: 20 AN: 15314

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00173 AC: 118 AN: 68020

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.00168 Hom.: 0

Bravo AF: 0.00131

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00202

EpiControl AF: 0.00124

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	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	-0.46
CADD	Benign	13
DANN	Benign	0.73
PhyloP100		5.0
Mutation Taster		=98/2	polymorphism

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: rs145907892; hg19: chr19-50139950;