5-87268470-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_002890.3(RASA1):c.19G>C(p.Gly7Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000143 in 1,399,510 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. G7S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: RASA1 NM_002890.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.35

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 2 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=0.3189518).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RASA1	NM_002890.3	c.19G>C	p.Gly7Arg	missense_variant	1/25	ENST00000274376.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RASA1	ENST00000274376.11	c.19G>C	p.Gly7Arg	missense_variant	1/25	1	NM_002890.3	P2
RASA1	ENST00000515800.6	c.19G>C	p.Gly7Arg	missense_variant, NMD_transcript_variant	1/26	1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000130 AC: 2 AN: 154314 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 82428

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000808

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000143 AC: 2 AN: 1399510 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 690202

Gnomad4 AFR exome AF: 0.0000314

Gnomad4 AMR exome AF: 0.0000280

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: 0.00

Gnomad4 OTH exome AF: 0.00

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

Jan 18, 2023

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 missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals affected with RASA1-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.008%). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 7 of the RASA1 protein (p.Gly7Arg). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.57
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.26
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.24	T
Eigen	Uncertain	0.26
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Benign	0.41	N
LIST_S2	Benign	0.85	D
M_CAP	Uncertain	0.29	D
MetaRNN	Benign	0.32	T
MetaSVM	Benign	-0.61	T
MutationAssessor	Benign	0.55	N
MutationTaster	Benign	0.81	D
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-0.30	N
REVEL	Uncertain	0.30
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.015	D
Polyphen		0.88	P
Vest4		0.37
MutPred		0.12		Loss of loop (P = 0.0128);
MVP		0.78
MPC		0.38
ClinPred		0.58	D
GERP RS		3.9
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.7
Varity_R		0.13
gMVP		0.35

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

LitVar

Other links and lift over

dbSNP: rs1250999130; hg19: chr5-86564287;