19-49635672-C-T

Variant names:

• chr19-49635672-C-T
• rs201690554
• NM_006270.5:c.573-12G>A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_006270.5(RRAS):​c.573-12G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00124 in 1,471,750 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 0.00089 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0013 (2 hom.)
• Consequence: RRAS NM_006270.5 intron
• Scores: Splicing: ADA: 0.0001718
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.156

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 19-49635672-C-T is Benign according to our data. Variant chr19-49635672-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 496319.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RRAS	NM_006270.5	c.573-12G>A		intron_variant	Intron 5 of 5	ENST00000246792.4	NP_006261.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RRAS	ENST00000246792.4	c.573-12G>A		intron_variant	Intron 5 of 5	1	NM_006270.5	ENSP00000246792.2
RRAS	ENST00000601532.1	n.*140G>A		downstream_gene_variant		5

Frequencies

GnomAD3 genomes AF: 0.000889 AC: 135 AN: 151868 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000387

Gnomad SAS AF: 0.00125

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00140

Gnomad OTH AF: 0.00192

GnomAD3 exomes AF: 0.000873 AC: 162 AN: 185492 Hom.: 0 AF XY: 0.000905 AC XY: 91 AN XY: 100544

Gnomad AFR exome AF: 0.000150

Gnomad AMR exome AF: 0.000823

Gnomad ASJ exome AF: 0.000173

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00111

Gnomad FIN exome AF: 0.000105

Gnomad NFE exome AF: 0.00129

Gnomad OTH exome AF: 0.000491

GnomAD4 exome AF: 0.00128 AC: 1686 AN: 1319764 Hom.: 2 Cov.: 30 AF XY: 0.00122 AC XY: 789 AN XY: 647692

Gnomad4 AFR exome AF: 0.000242

Gnomad4 AMR exome AF: 0.000729

Gnomad4 ASJ exome AF: 0.0000485

Gnomad4 EAS exome AF: 0.0000291

Gnomad4 SAS exome AF: 0.00102

Gnomad4 FIN exome AF: 0.0000613

Gnomad4 NFE exome AF: 0.00148

Gnomad4 OTH exome AF: 0.000995

GnomAD4 genome AF: 0.000888 AC: 135 AN: 151986 Hom.: 0 Cov.: 31 AF XY: 0.000969 AC XY: 72 AN XY: 74276

Gnomad4 AFR AF: 0.000241

Gnomad4 AMR AF: 0.00118

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000387

Gnomad4 SAS AF: 0.00125

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00140

Gnomad4 OTH AF: 0.00190

Alfa AF: 0.000825 Hom.: 1

Bravo AF: 0.000854

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Nov 22, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 11, 2017

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The RRAS c.573-12G>A variant involves the alteration of a non-conserved intronic nucleotide. Mutation Taster predicts a benign outcome for this variant. 4/5 splice prediction tools predict no significant impact on normal splicing. This variant was found in 96/111944 control chromosomes from ExAC at a frequency of 0.0008576, which is approximately 343 times the estimated maximal expected allele frequency of a pathogenic RRAS variant (0.0000025), suggesting this variant is likely a benign polymorphism. The variant of interest has not, to our knowledge, been reported in affected individuals via publications. Taken together, this variant is classified as Benign. -

Noonan syndrome Benign:1

Jan 27, 2025

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	-0.72
CADD	Benign	14
DANN	Benign	0.75

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00017
dbscSNV1_RF	Benign	0.0
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: rs201690554; hg19: chr19-50138929;