rs137853218

chr5-87333291-C-T

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.853C>T(p.Arg285Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.000000685 in 1,460,742 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: RASA1 NM_002890.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 3.70

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]

CCNH (HGNC:1594): (cyclin H) The protein encoded by this gene belongs to the highly conserved cyclin family, whose members are characterized by a dramatic periodicity in protein abundance through the cell cycle. Cyclins function as regulators of CDK kinases. Different cyclins exhibit distinct expression and degradation patterns which contribute to the temporal coordination of each mitotic event. This cyclin forms a complex with CDK7 kinase and ring finger protein MAT1. The kinase complex is able to phosphorylate CDK2 and CDC2 kinases, thus functions as a CDK-activating kinase (CAK). This cyclin and its kinase partner are components of TFIIH, as well as RNA polymerase II protein complexes. They participate in two different transcriptional regulation processes, suggesting an important link between basal transcription control and the cell cycle machinery. A pseudogene of this gene is found on chromosome 4. Alternate splicing results in multiple transcript variants.[provided by RefSeq, Nov 2010]

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 5-87333291-C-T is Pathogenic according to our data. Variant chr5-87333291-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 16001.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-87333291-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RASA1	NM_002890.3	c.853C>T	p.Arg285Ter	stop_gained	4/25	ENST00000274376.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RASA1	ENST00000274376.11	c.853C>T	p.Arg285Ter	stop_gained	4/25	1	NM_002890.3	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460742 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 726626

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: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Capillary malformation-arteriovenous malformation 1 Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	May 01, 2008	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Jun 24, 2022	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with capillary malformation-arteriovenous malformation 1 (MIM#608354). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been observed in five unrelated individuals with capillary malformation-arteriovenous malformation, including two de novo cases and one family where the variant segregated in several affected members (PMIDs: 29891884, 25040287, 18363760, 24038909). (SP) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Capillary malformation-arteriovenous malformation syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Mar 20, 2023

Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 16001). This premature translational stop signal has been observed in individual(s) with capillary malformation (PMID: 18363760, 25040287). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg285*) 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). For these reasons, this variant has been classified as Pathogenic. -

Vascular malformation Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Clinical Genomics Laboratory, Washington University in St. Louis

Sep 06, 2023

The RASA1 c.853C>T (p.Arg285Ter) variant was identified at an allelic fraction consistent with somatic origin. This variant has been reported in multiple individuals with vascular malformations (Hershkovitz D et al., PMID: 18363760; Revencu N et al., PMID: 24038909; Weitz NA et al., PMID: 25040287; Wooderchak-Donahue WL et al., PMID: 29891884). This variant has been reported in the ClinVar database as a germline pathogenic variant by one submitter (ClinVar ID: 16001) and in multiple cases in the cancer database CbioPortal. This variant is absent from the general population (gnomAD v.3.1.2), indicating that it is not a common variant. The RASA1 c.853C>T (p.Arg285Ter) variant causes a premature truncation codon, which is predicted to result in nonsense-mediated decay, and loss of function is the known disease mechanism (Revencu N et al., PMID: 24038909). Based on an internally-developed protocol informed by the ACMG/AMP guidelines (Richards S et al., PMID: 25741868) and gene-specific practices from the ClinGen Criteria Specification Registry, the RASA1 c.853C>T (p.Arg285Ter) variant is classified as pathogenic. -

RASA1-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 28, 2023

The RASA1 c.853C>T variant is predicted to result in premature protein termination (p.Arg285*). This variant has been reported as segregating with disease in a large kindred with capillary malformations (Hershkovitz et al. 2008. PubMed ID: 18363760) and in other unrelated individuals with capillary malformations (Weitz et al. 2014. PubMed ID: 25040287; Wooderchak-Donahue et al. 2018. PubMed ID: 29891884). This variant has not been reported in a large population database, indicating this variant is rare. Nonsense variants in RASA1 are expected to be pathogenic. Given the evidence, we interpret this variant as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.62
Cadd	Pathogenic	44
Dann	Uncertain	1.0
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	0.98	D
MutationTaster	Benign	1.0	A;A;A;A
Vest4		0.91
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.21		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.21		Position offset: -24

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs137853218; hg19: chr5-86629108; COSMIC: COSV57192495; COSMIC: COSV57192495;