5-87268613-G-C

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_002890.3(RASA1):c.162G>C(p.Glu54Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000139 in 1,612,110 control chromosomes in the GnomAD database, including 1 homozygotes. 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000085 (1 hom.)
• Consequence: RASA1 NM_002890.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.567

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 Benign. Variant got -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, RASA1
• BP4: Computational evidence support a benign effect (MetaRNN=0.006025046).
• BP6: Variant 5-87268613-G-C is Benign according to our data. Variant chr5-87268613-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 464852.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000657 (100/152320) while in subpopulation AFR AF= 0.00228 (95/41578). AF 95% confidence interval is 0.00191. There are 0 homozygotes in gnomad4. There are 51 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 100 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RASA1	NM_002890.3	c.162G>C	p.Glu54Asp	missense_variant	1/25	ENST00000274376.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RASA1	ENST00000274376.11	c.162G>C	p.Glu54Asp	missense_variant	1/25	1	NM_002890.3	P2
RASA1	ENST00000515800.6	c.162G>C	p.Glu54Asp	missense_variant, NMD_transcript_variant	1/26	1

Frequencies

GnomAD3 genomes AF: 0.000657 AC: 100 AN: 152202 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00229

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000182 AC: 44 AN: 241984 Hom.: 1 AF XY: 0.000114 AC XY: 15 AN XY: 132082

Gnomad AFR exome AF: 0.00267

Gnomad AMR exome AF: 0.000147

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: 0.0000849 AC: 124 AN: 1459790 Hom.: 1 Cov.: 32 AF XY: 0.0000716 AC XY: 52 AN XY: 726048

Gnomad4 AFR exome AF: 0.00281

Gnomad4 AMR exome AF: 0.000202

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.000249

GnomAD4 genome AF: 0.000657 AC: 100 AN: 152320 Hom.: 0 Cov.: 32 AF XY: 0.000685 AC XY: 51 AN XY: 74476

Gnomad4 AFR AF: 0.00228

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000124 Hom.: 0

Bravo AF: 0.000816

ESP6500AA AF: 0.00116 AC: 5

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000215 AC: 26

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Capillary malformation-arteriovenous malformation syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 21, 2024

- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 20, 2020

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

RASA1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 11, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Capillary malformation-arteriovenous malformation 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.50
Cadd	Benign	14
Dann	Uncertain	0.98
DEOGEN2	Benign	0.22	T
Eigen	Benign	-0.82
Eigen_PC	Benign	-0.73
FATHMM_MKL	Benign	0.011	N
LIST_S2	Benign	0.63	T
M_CAP	Benign	0.078	D
MetaRNN	Benign	0.0060	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.20	N
MutationTaster	Benign	1.0	N
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	0.11	N
REVEL	Benign	0.082
Sift	Benign	0.44	T
Sift4G	Benign	0.71	T
Polyphen		0.059	B
Vest4		0.094
MutPred		0.39		Loss of sheet (P = 0.0126);
MVP		0.63
MPC		0.090
ClinPred		0.022	T
GERP RS		1.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.057
gMVP		0.074

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: rs201502793; hg19: chr5-86564430;