5-87268747-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_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. 15/21 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

Publications

12 publications found

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 Gene-Disease associations (from GenCC):

capillary malformation-arteriovenous malformation 1
Inheritance: AD Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics, G2P
capillary malformation-arteriovenous malformation syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Parkes Weber syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
cardiofaciocutaneous syndrome
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
Costello syndrome
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
Noonan syndrome
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
Noonan syndrome with multiple lentigines
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
Noonan syndrome-like disorder with loose anagen hair
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
telangiectasia, hereditary hemorrhagic, type 1
Inheritance: AD Classification: NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae)

RASA1 links:

ENSG00000303897 (HGNC:):

ENSG00000303897 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

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 Benign/Likely_benign. ClinVar VariationId is 213659.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 3051 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002890.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RASA1	NM_002890.3	MANE Select	c.296C>T	p.Ala99Val	missense	Exon 1 of 25	NP_002881.1	P20936-1
	RASA1	NM_022650.3		c.-301C>T		upstream_gene	N/A	NP_072179.1	P20936-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RASA1	ENST00000274376.11	TSL:1 MANE Select	c.296C>T	p.Ala99Val	missense	Exon 1 of 25	ENSP00000274376.6	P20936-1
RASA1	ENST00000515800.6	TSL:1	n.296C>T		non_coding_transcript_exon	Exon 1 of 26	ENSP00000423395.2	P20936-3
RASA1	ENST00000888490.1		c.296C>T	p.Ala99Val	missense	Exon 1 of 25	ENSP00000558549.1

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

GnomAD2 exomes

AF:

0.0188

AC:

4681

AN:

248948

AF XY:

0.0191

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 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

African (AFR)

AF:

0.00496

AC:

166

AN:

33478

American (AMR)

AF:

0.0173

AC:

771

AN:

44590

Ashkenazi Jewish (ASJ)

AF:

0.0164

AC:

427

AN:

26096

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39690

South Asian (SAS)

AF:

0.00565

AC:

487

AN:

86214

European-Finnish (FIN)

AF:

0.00704

AC:

375

AN:

53266

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

5752

European-Non Finnish (NFE)

AF:

0.0329

AC:

36622

AN:

1111738

Other (OTH)

AF:

0.0240

AC:

1446

AN:

60348

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

2747

5495

8242

10990

13737

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1342

2684

4026

5368

6710

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0200

AC:

3051

AN:

152274

Hom.:

Cov.:

AF XY:

0.0180

AC XY:

1341

AN XY:

74458

show subpopulations

African (AFR)

AF:

0.00616

AC:

256

AN:

41570

American (AMR)

AF:

0.0288

AC:

440

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.0156

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00435

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00509

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.0204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0307

AC:

2089

AN:

68002

Other (OTH)

AF:

0.0255

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

163

326

490

653

816

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

128

160

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0260

Hom.:

102

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

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (4)

not provided (3)

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

Capillary malformation-arteriovenous malformation 1 (1)

Capillary malformation-arteriovenous malformation syndrome (1)

Cardiovascular phenotype (1)

Parkes Weber syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.47

CADD

Benign

(source)

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

PhyloP100

-0.051

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

PromoterAI

0.021

Neutral

(source)

Varity_R

0.037

gMVP

0.24

Mutation Taster

=96/4

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over