chr5-87268747-C-T

Position:

chr5-87268747-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBS1BS2

The NM_002890.3(RASA1):c.296C>T(p.Ala99Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0269 in 1,613,446 control chromosomes in the GnomAD database, including 745 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.020 ( 43 hom., cov: 32)

Exomes 𝑓: 0.028 ( 702 hom. )

Consequence

RASA1
NM_002890.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: -0.0510

Variant links:

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]

RASA1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), RASA1. . Gene score misZ 3.0984 (greater than the threshold 3.09). Trascript score misZ 3.5912 (greater than threshold 3.09). GenCC has associacion of gene with capillary malformation-arteriovenous malformation syndrome, Parkes Weber syndrome, Noonan syndrome, telangiectasia, hereditary hemorrhagic, type 1, capillary malformation-arteriovenous malformation 1.

BP4

Computational evidence support a benign effect (MetaRNN=0.0021522343).

BP6

Variant 5-87268747-C-T is Benign according to our data. Variant chr5-87268747-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 213659.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-87268747-C-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.02 (3051/152274) while in subpopulation NFE AF= 0.0307 (2089/68002). AF 95% confidence interval is 0.0296. There are 43 homozygotes in gnomad4. There are 1341 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 3051 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RASA1	NM_002890.3 linkuse as main transcript	c.296C>T	p.Ala99Val	missense_variant	1/25	ENST00000274376.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RASA1	ENST00000274376.11 linkuse as main transcript	c.296C>T	p.Ala99Val	missense_variant	1/25	1	NM_002890.3	P2	P20936-1
RASA1	ENST00000515800.6 linkuse as main transcript	c.296C>T	p.Ala99Val	missense_variant, NMD_transcript_variant	1/26	1			P20936-3

Frequencies

GnomAD3 genomes

AF:

0.0201

AC:

3054

AN:

152156

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00618

Gnomad AMI

AF:

0.0844

Gnomad AMR

AF:

0.0288

Gnomad ASJ

AF:

0.0156

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00435

Gnomad FIN

AF:

0.00509

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.0307

Gnomad OTH

AF:

0.0258

GnomAD3 exomes

AF:

0.0188

AC:

4681

AN:

248948

Hom.:

AF XY:

0.0191

AC XY:

2581

AN XY:

134840

show subpopulations

Gnomad AFR exome

AF:

0.00542

Gnomad AMR exome

AF:

0.0163

Gnomad ASJ exome

AF:

0.0178

Gnomad EAS exome

AF:

0.0000545

Gnomad SAS exome

AF:

0.00553

Gnomad FIN exome

AF:

0.00665

Gnomad NFE exome

AF:

0.0303

Gnomad OTH exome

AF:

0.0234

GnomAD4 exome

AF:

0.0276

AC:

40393

AN:

1461172

Hom.:

702

Cov.:

AF XY:

0.0268

AC XY:

19516

AN XY:

726900

show subpopulations

Gnomad4 AFR exome

AF:

0.00496

Gnomad4 AMR exome

AF:

0.0173

Gnomad4 ASJ exome

AF:

0.0164

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00565

Gnomad4 FIN exome

AF:

0.00704

Gnomad4 NFE exome

AF:

0.0329

Gnomad4 OTH exome

AF:

0.0240

GnomAD4 genome

AF:

0.0200

AC:

3051

AN:

152274

Hom.:

Cov.:

AF XY:

0.0180

AC XY:

1341

AN XY:

74458

show subpopulations

Gnomad4 AFR

AF:

0.00616

Gnomad4 AMR

AF:

0.0288

Gnomad4 ASJ

AF:

0.0156

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00435

Gnomad4 FIN

AF:

0.00509

Gnomad4 NFE

AF:

0.0307

Gnomad4 OTH

AF:

0.0255

Alfa

AF:

0.0271

Hom.:

Bravo

AF:

0.0210

TwinsUK

AF:

0.0289

AC:

107

ALSPAC

AF:

0.0343

AC:

132

ESP6500AA

AF:

0.00794

AC:

ESP6500EA

AF:

0.0286

AC:

246

ExAC

AF:

0.0187

AC:

2272

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 12, 2016	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 17, 2015	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided

Benign:3

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2023	RASA1: BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 22, 2023	- -

Basal cell carcinoma, susceptibility to, 1;C4747394:Capillary malformation-arteriovenous malformation 1

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Feb 07, 2022

- -

Capillary malformation-arteriovenous malformation syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Parkes Weber syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 21, 2015

This alteration is classified as 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. -

Capillary malformation-arteriovenous malformation 1

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.47

CADD

Benign

DANN

Benign

0.87

DEOGEN2

Benign

0.24

Eigen

Benign

-0.64

Eigen_PC

Benign

-0.71

FATHMM_MKL

Benign

0.23

LIST_S2

Benign

0.75

MetaRNN

Benign

0.0022

MetaSVM

Benign

-0.95

MutationAssessor

Benign

0.0

MutationTaster

Benign

0.99

PrimateAI

Uncertain

0.75

PROVEAN

Benign

-0.34

REVEL

Benign

0.19

Sift

Benign

0.25

Sift4G

Benign

0.12

Polyphen

0.33

Vest4

0.15

MPC

0.17

ClinPred

0.014

GERP RS

0.62

Varity_R

0.037

gMVP

0.24

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over