chr19-49635633-C-T

Variant names:

• chr19-49635633-C-T
• rs183538580
• NM_006270.5:c.600G>A

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM2 BP4_Strong BP6_Very_Strong BP7

The NM_006270.5(RRAS):​c.600G>A​(p.Pro200Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000184 in 1,446,130 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00018 (1 hom.)
• Consequence: RRAS NM_006270.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.322

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]

ACMG classification

Verdict is Benign. Variant got -11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant 19-49635633-C-T is Benign according to our data. Variant chr19-49635633-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 457990.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.322 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RRAS	NM_006270.5	c.600G>A	p.Pro200Pro	synonymous_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.600G>A	p.Pro200Pro	synonymous_variant	Exon 6 of 6	1	NM_006270.5	ENSP00000246792.2
RRAS	ENST00000601532.1	n.*179G>A		downstream_gene_variant		5

Frequencies

GnomAD3 genomes AF: 0.000204 AC: 31 AN: 151950 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00309

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000736

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000333 AC: 54 AN: 162148 Hom.: 0 AF XY: 0.000242 AC XY: 21 AN XY: 86704

Gnomad AFR exome AF: 0.000233

Gnomad AMR exome AF: 0.000271

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00348

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000569

Gnomad NFE exome AF: 0.0000622

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000182 AC: 235 AN: 1294062 Hom.: 1 Cov.: 31 AF XY: 0.000180 AC XY: 114 AN XY: 632646

Gnomad4 AFR exome AF: 0.000108

Gnomad4 AMR exome AF: 0.000221

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00520

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000441

Gnomad4 OTH exome AF: 0.0000959

GnomAD4 genome AF: 0.000204 AC: 31 AN: 152068 Hom.: 0 Cov.: 31 AF XY: 0.000242 AC XY: 18 AN XY: 74332

Gnomad4 AFR AF: 0.000145

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00310

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000736

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000132 Hom.: 0

Bravo AF: 0.000151

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Jan 19, 2020

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 02, 2022

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

RRAS-related disorder Benign:1

Mar 22, 2019

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Noonan syndrome Benign:1

Nov 23, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	12
DANN	Benign	0.58

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

Publications

LitVar

Other links and lift over

dbSNP: rs183538580; hg19: chr19-50138890; COSMIC: COSV55868476; COSMIC: COSV55868476;