19-49635861-A-C

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_006270.5(RRAS):​c.454-9T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000141 in 327,034 control chromosomes in the GnomAD database, with no homozygous occurrence. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 26)
  • Exomes 𝑓: 0.00014 (0 hom.)
• Consequence: RRAS NM_006270.5 intron
• Scores: Splicing: ADA: 0.0006961
• Clinical Significance: Not reported in ClinVar
• 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes Cov.: 26

GnomAD4 exome AF: 0.000141 AC: 46 AN: 327034 Hom.: 0 Cov.: 10 AF XY: 0.000112 AC XY: 20 AN XY: 178512

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

African (AFR) AF: 0.000507 AC: 5 AN: 9856

American (AMR) AF: 0.00 AC: 0 AN: 18938

Ashkenazi Jewish (ASJ) AF: 0.000210 AC: 2 AN: 9510

East Asian (EAS) AF: 0.00 AC: 0 AN: 11886

South Asian (SAS) AF: 0.0000393 AC: 2 AN: 50932

European-Finnish (FIN) AF: 0.0000854 AC: 2 AN: 23410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1784

European-Non Finnish (NFE) AF: 0.000176 AC: 33 AN: 187024

Other (OTH) AF: 0.000146 AC: 2 AN: 13694

⚠️ 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 Cov.: 26

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	2.8
DANN	Benign	0.54
PhyloP100		0.25

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00070
dbscSNV1_RF	Benign	0.068
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;