rs199675852

Variant names:

• chr19-49635572-T-C
• rs199675852
• NM_006270.5:c.*4A>G

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_006270.5(RRAS):​c.*4A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000397 in 1,423,338 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00062 (1 hom., cov: 31)
  • Exomes 𝑓: 0.00037 (1 hom.)
• Consequence: RRAS NM_006270.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.14
• Publications: 1 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, 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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 19-49635572-T-C is Benign according to our data. Variant chr19-49635572-T-C is described in ClinVar as Benign. ClinVar VariationId is 928938.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 94 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.*4A>G		3_prime_UTR	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.*4A>G		3_prime_UTR	Exon 6 of 6	ENSP00000246792.2	P10301
	RRAS	ENST00000962270.1		c.*4A>G		3_prime_UTR	Exon 7 of 7	ENSP00000632329.1
	RRAS	ENST00000928399.1		c.*4A>G		3_prime_UTR	Exon 6 of 6	ENSP00000598458.1

Frequencies

GnomAD3 genomes AF: 0.000620 AC: 94 AN: 151718 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000132

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0171

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.00158 AC: 236 AN: 149148 AF XY: 0.00136

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0210

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000651

GnomAD4 exome AF: 0.000370 AC: 471 AN: 1271498 Hom.: 1 Cov.: 29 AF XY: 0.000330 AC XY: 204 AN XY: 618632

African (AFR) AF: 0.00 AC: 0 AN: 27590

American (AMR) AF: 0.00 AC: 0 AN: 23646

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17570

East Asian (EAS) AF: 0.0126 AC: 429 AN: 33994

South Asian (SAS) AF: 0.00 AC: 0 AN: 54458

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46808

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4692

European-Non Finnish (NFE) AF: 9.89e-7 AC: 1 AN: 1011308

Other (OTH) AF: 0.000797 AC: 41 AN: 51432

GnomAD4 genome AF: 0.000619 AC: 94 AN: 151840 Hom.: 1 Cov.: 31 AF XY: 0.000607 AC XY: 45 AN XY: 74194

African (AFR) AF: 0.00 AC: 0 AN: 41396

American (AMR) AF: 0.000131 AC: 2 AN: 15228

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

East Asian (EAS) AF: 0.0171 AC: 88 AN: 5132

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10512

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67980

Other (OTH) AF: 0.00143 AC: 3 AN: 2104

Alfa AF: 0.000125 Hom.: 0

Bravo AF: 0.000752

Asia WGS AF: 0.00346 AC: 12 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.80
DANN	Benign	0.51
PhyloP100		-1.1
Mutation Taster		=100/0	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: rs199675852; hg19: chr19-50138829;