chr19-49639980-ACGC-A

Variant names:

• chr19-49639980-ACGC-A
• rs749539343
• NM_006270.5:c.116_118delGCG

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PM4_Supporting

The NM_006270.5(RRAS):​c.116_118delGCG​(p.Gly39del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.00000835 in 1,436,542 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000084 (0 hom.)
• Consequence: RRAS NM_006270.5 disruptive_inframe_deletion
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.65
• Publications: 4 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: Uncertain_significance. The variant received 1 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_006270.5. Strenght limited to Supporting due to length of the change: 1aa.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RRAS	NM_006270.5	c.116_118delGCG	p.Gly39del	disruptive_inframe_deletion	Exon 1 of 6	ENST00000246792.4	NP_006261.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RRAS	ENST00000246792.4	c.116_118delGCG	p.Gly39del	disruptive_inframe_deletion	Exon 1 of 6	1	NM_006270.5	ENSP00000246792.2
RRAS	ENST00000601532.1	n.140_142delGCG		non_coding_transcript_exon_variant	Exon 1 of 4	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000572 AC: 12 AN: 209922 AF XY: 0.0000684

Gnomad AFR exome AF: 0.0000899

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000110

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000782

Gnomad NFE exome AF: 0.0000836

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000835 AC: 12 AN: 1436542 Hom.: 0 AF XY: 0.00000980 AC XY: 7 AN XY: 714624

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

African (AFR) AF: 0.0000631 AC: 2 AN: 31702

American (AMR) AF: 0.00 AC: 0 AN: 43562

Ashkenazi Jewish (ASJ) AF: 0.0000390 AC: 1 AN: 25620

East Asian (EAS) AF: 0.00 AC: 0 AN: 37542

South Asian (SAS) AF: 0.0000236 AC: 2 AN: 84766

European-Finnish (FIN) AF: 0.0000471 AC: 2 AN: 42462

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5500

European-Non Finnish (NFE) AF: 0.00000452 AC: 5 AN: 1105828

Other (OTH) AF: 0.00 AC: 0 AN: 59560

⚠️ 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.: 32

Alfa AF: 0.000557 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.6
Mutation Taster		=18/82	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs749539343; hg19: chr19-50143237;