5-87268699-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_002890.3(RASA1):c.248G>T(p.Gly83Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G83E) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RASA1 NM_002890.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.55

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, RASA1
• BP4: Computational evidence support a benign effect (MetaRNN=0.21638754).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RASA1	NM_002890.3	c.248G>T	p.Gly83Val	missense_variant	1/25	ENST00000274376.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RASA1	ENST00000274376.11	c.248G>T	p.Gly83Val	missense_variant	1/25	1	NM_002890.3	P2
RASA1	ENST00000515800.6	c.248G>T	p.Gly83Val	missense_variant, NMD_transcript_variant	1/26	1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Capillary malformation-arteriovenous malformation syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Oct 30, 2020

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with RASA1-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with valine at codon 83 of the RASA1 protein (p.Gly83Val). The glycine residue is weakly conserved and there is a moderate physicochemical difference between glycine and valine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.0098	T
BayesDel_noAF	Benign	-0.25
Cadd	Benign	17
Dann	Benign	0.97
DEOGEN2	Benign	0.24	T
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.35
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.79	T
M_CAP	Uncertain	0.26	D
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	0.34	N
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-0.29	N
REVEL	Benign	0.23
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.014	D
Polyphen		0.32	B
Vest4		0.34
MutPred		0.23		Loss of loop (P = 0.0512);
MVP		0.74
MPC		0.38
ClinPred		0.69	D
GERP RS		2.1
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.1
Varity_R		0.077
gMVP		0.48

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-86564516;