rs797044451

Positions:

• chr5-87268921-ACT-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_002890.3(RASA1):​c.475_476delCT​(p.Leu159fs) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000137 in 1,461,892 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: RASA1 NM_002890.3 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 3.85

Genes affected

RASA1 (HGNC:9871): (RAS p21 protein activator 1) The protein encoded by this gene is located in the cytoplasm and is part of the GAP1 family of GTPase-activating proteins. The gene product stimulates the GTPase activity of normal RAS p21 but not its oncogenic counterpart. Acting as a suppressor of RAS function, the protein enhances the weak intrinsic GTPase activity of RAS proteins resulting in the inactive GDP-bound form of RAS, thereby allowing control of cellular proliferation and differentiation. Mutations leading to changes in the binding sites of either protein are associated with basal cell carcinomas. Mutations also have been associated with hereditary capillary malformations (CM) with or without arteriovenous malformations (AVM) and Parkes Weber syndrome. Alternative splicing results in two isoforms where the shorter isoform, lacking the N-terminal hydrophobic region but retaining the same activity, appears to be abundantly expressed in placental but not adult tissues. [provided by RefSeq, May 2012]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-87268921-ACT-A is Pathogenic according to our data. Variant chr5-87268921-ACT-A is described in ClinVar as [Pathogenic]. Clinvar id is 15999.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-87268921-ACT-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RASA1	NM_002890.3	c.475_476delCT	p.Leu159fs	frameshift_variant	1/25	ENST00000274376.11	NP_002881.1
RASA1	NM_022650.3	c.-126_-125delCT		upstream_gene_variant			NP_072179.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RASA1	ENST00000274376.11	c.475_476delCT	p.Leu159fs	frameshift_variant	1/25	1	NM_002890.3	ENSP00000274376.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461892 Hom.: 0 AF XY: 0.00000138 AC XY: 1 AN XY: 727246

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 30, 2023	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 14639529, 29891884, 31263281) -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Oct 26, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jun 26, 2018	The RASA1 c.475_476delCT; p.Leu159fs variant (rs797044451), is reported in the literature in one family and two individuals affected with capillary malformations and/or arteriovenous malformations (Eerola 2003 and Revencu 2013). This variant is classified as pathogenic in ClinVar (Variation ID: 15999), and it is absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database). This variant causes a frameshift by deleting two nucleotides, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Truncating, loss-of-function variants in RASA1 are an established mechanism of disease. Therefore, based on available information, this variant is considered pathogenic. -

Gorham-Stout disease Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital

May 14, 2021

This sequence change deletes two nucleotides in exon 1 of the RASA1 mRNA, leading to a frameshift and insertion of a premature stop codon. This transcript is predicted to undergo nonsense mediated degradation, leading to RASA1 haploinsufficiency. This variant is absent from population databases and present in patient databases (ClinVar Allele ID: 31038). RASA1 c.475_476delCT has been reported in multiple individuals with capillary malformations and/or arteriovenous malformations (PMID: 14639529, PMID: 15917201, PMID: 29891884). -

Capillary malformation-arteriovenous malformation syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 03, 2023

This sequence change creates a premature translational stop signal (p.Leu159Glyfs*20) in the RASA1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in RASA1 are known to be pathogenic (PMID: 24038909). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with clinical features of RASA1-related conditions (PMID: 14639529). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 15999). For these reasons, this variant has been classified as Pathogenic. -

Capillary malformation-arteriovenous malformation 1 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 01, 2003

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs797044451; hg19: chr5-86564738;