19-49635861-A-G

Variant names:

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

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>C 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 0.00018 (0 hom., cov: 26)
  • Exomes 𝑓: 0.0015 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: RRAS NM_006270.5 intron
• Scores: Splicing: ADA: 0.00005769
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• 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=-0.88).
• BP6: Variant 19-49635861-A-G is Benign according to our data. Variant chr19-49635861-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 457989.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>C		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>C		intron_variant	Intron 4 of 5	1	NM_006270.5	ENSP00000246792.2
RRAS	ENST00000601532.1	n.594-9T>C		intron_variant	Intron 3 of 3	5

Frequencies

GnomAD3 genomes AF: 0.000180 AC: 17 AN: 94644 Hom.: 0 Cov.: 26

Gnomad AFR AF: 0.000112

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00107

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000488

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000866

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000271 AC: 40 AN: 147664 AF XY: 0.000277

Gnomad AFR exome AF: 0.000107

Gnomad AMR exome AF: 0.000595

Gnomad ASJ exome AF: 0.000619

Gnomad EAS exome AF: 0.000442

Gnomad FIN exome AF: 0.000140

Gnomad NFE exome AF: 0.000194

Gnomad OTH exome AF: 0.000294

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00152 AC: 497 AN: 326264 Hom.: 0 Cov.: 10 AF XY: 0.00148 AC XY: 263 AN XY: 178060

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

African (AFR) AF: 0.00163 AC: 16 AN: 9844

American (AMR) AF: 0.00329 AC: 62 AN: 18828

Ashkenazi Jewish (ASJ) AF: 0.00179 AC: 17 AN: 9476

East Asian (EAS) AF: 0.000843 AC: 10 AN: 11856

South Asian (SAS) AF: 0.00183 AC: 93 AN: 50788

European-Finnish (FIN) AF: 0.00180 AC: 42 AN: 23352

Middle Eastern (MID) AF: 0.00112 AC: 2 AN: 1784

European-Non Finnish (NFE) AF: 0.00126 AC: 236 AN: 186672

Other (OTH) AF: 0.00139 AC: 19 AN: 13664

⚠️ 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: 0.000180 AC: 17 AN: 94690 Hom.: 0 Cov.: 26 AF XY: 0.000270 AC XY: 12 AN XY: 44464

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

African (AFR) AF: 0.000112 AC: 3 AN: 26796

American (AMR) AF: 0.00107 AC: 8 AN: 7490

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 2734

South Asian (SAS) AF: 0.00 AC: 0 AN: 2954

European-Finnish (FIN) AF: 0.000488 AC: 2 AN: 4098

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

European-Non Finnish (NFE) AF: 0.0000866 AC: 4 AN: 46194

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.

Alfa AF: 0.0201 Hom.: 0

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Mar 28, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Noonan syndrome Benign:1

Feb 09, 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	-0.88
CADD	Benign	2.8
DANN	Benign	0.49
PhyloP100		0.25
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000058
dbscSNV1_RF	Benign	0.0
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; COSMIC: COSV55868131;