19-49635861-A-T

Variant names:

• chr19-49635861-A-T
• rs1490597941
• NM_006270.5:c.454-9T>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_006270.5(RRAS):​c.454-9T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000021 (0 hom., cov: 26)
  • Exomes 𝑓: 0.0084 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: RRAS NM_006270.5 intron
• Scores: Splicing: ADA: 0.0006494
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.252
• 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: ClinGen, Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 19-49635861-A-T is Benign according to our data. Variant chr19-49635861-A-T is described in ClinVar as Likely_benign. ClinVar VariationId is 759077.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RRAS	NM_006270.5	c.454-9T>A		intron_variant	Intron 4 of 5	ENST00000246792.4	NP_006261.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RRAS	ENST00000246792.4	c.454-9T>A		intron_variant	Intron 4 of 5	1	NM_006270.5	ENSP00000246792.2
RRAS	ENST00000601532.1	n.594-9T>A		intron_variant	Intron 3 of 3	5

Frequencies

GnomAD3 genomes AF: 0.0000211 AC: 2 AN: 94696 Hom.: 0 Cov.: 26

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000365

Gnomad SAS AF: 0.000338

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00838 AC: 2721 AN: 324662 Hom.: 0 Cov.: 10 AF XY: 0.00760 AC XY: 1348 AN XY: 177404

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00499 AC: 49 AN: 9824

American (AMR) AF: 0.00132 AC: 25 AN: 18902

Ashkenazi Jewish (ASJ) AF: 0.00328 AC: 31 AN: 9444

East Asian (EAS) AF: 0.00693 AC: 81 AN: 11696

South Asian (SAS) AF: 0.000747 AC: 38 AN: 50894

European-Finnish (FIN) AF: 0.000471 AC: 11 AN: 23376

Middle Eastern (MID) AF: 0.00224 AC: 4 AN: 1782

European-Non Finnish (NFE) AF: 0.0129 AC: 2389 AN: 185164

Other (OTH) AF: 0.00685 AC: 93 AN: 13580

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000211 AC: 2 AN: 94742 Hom.: 0 Cov.: 26 AF XY: 0.0000225 AC XY: 1 AN XY: 44490

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 26808

American (AMR) AF: 0.00 AC: 0 AN: 7512

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2458

East Asian (EAS) AF: 0.000366 AC: 1 AN: 2734

South Asian (SAS) AF: 0.000339 AC: 1 AN: 2954

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 4098

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 196

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 46212

Other (OTH) AF: 0.00 AC: 0 AN: 1190

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

RRAS-related disorder Benign:1

Jan 16, 2020

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). -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Noonan syndrome Benign:1

Aug 13, 2018

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	-0.83
CADD	Benign	2.6
DANN	Benign	0.63
PhyloP100		0.25

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00065
dbscSNV1_RF	Benign	0.056
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: rs1490597941; hg19: chr19-50139118;