rs111840875

chr5-87268747-C-T

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.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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.0510

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=0.0021522343).
• 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. This position pass quality control queck.
• BS2: High AC in GnomAd at 3054 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RASA1	NM_002890.3	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	c.296C>T	p.Ala99Val	missense_variant	1/25	1	NM_002890.3	P2
RASA1	ENST00000515800.6	c.296C>T	p.Ala99Val	missense_variant, NMD_transcript_variant	1/26	1

Frequencies

GnomAD3 genomes AF: 0.0201 AC: 3054 AN: 152156 Hom.: 43 Cov.: 32

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.: 66 AF XY: 0.0191 AC XY: 2581 AN XY: 134840

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.: 33 AF XY: 0.0268 AC XY: 19516 AN XY: 726900

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.: 43 Cov.: 32 AF XY: 0.0180 AC XY: 1341 AN XY: 74458

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.: 82

Bravo AF: 0.0210

TwinsUK AF: 0.0289 AC: 107

ALSPAC AF: 0.0343 AC: 132

ESP6500AA AF: 0.00794 AC: 35

ESP6500EA AF: 0.0286 AC: 246

ExAC AF: 0.0187 AC: 2272

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

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:2

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

- -

Parkes Weber syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Capillary malformation-arteriovenous malformation syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

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	T
BayesDel_noAF	Benign	-0.47
Cadd	Benign	17
Dann	Benign	0.87
DEOGEN2	Benign	0.24	T
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.71
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.75	T
MetaRNN	Benign	0.0022	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.0	N
MutationTaster	Benign	0.99	D
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-0.34	N
REVEL	Benign	0.19
Sift	Benign	0.25	T
Sift4G	Benign	0.12	T
Polyphen		0.33	B
Vest4		0.15
MPC		0.17
ClinPred		0.014	T
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

Other links and lift over

dbSNP: rs111840875; hg19: chr5-86564564;