rs184201084

Variant names:

Your query was ambiguous. Multiple possible variants found:

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.2528C>A(p.Thr843Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000456 in 1,612,684 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T843A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00064 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00044 ( 9 hom. )

Consequence

RASA1
NM_002890.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 5.55

Publications

6 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 links:

CCNH (HGNC:1594): (cyclin H) The protein encoded by this gene belongs to the highly conserved cyclin family, whose members are characterized by a dramatic periodicity in protein abundance through the cell cycle. Cyclins function as regulators of CDK kinases. Different cyclins exhibit distinct expression and degradation patterns which contribute to the temporal coordination of each mitotic event. This cyclin forms a complex with CDK7 kinase and ring finger protein MAT1. The kinase complex is able to phosphorylate CDK2 and CDC2 kinases, thus functions as a CDK-activating kinase (CAK). This cyclin and its kinase partner are components of TFIIH, as well as RNA polymerase II protein complexes. They participate in two different transcriptional regulation processes, suggesting an important link between basal transcription control and the cell cycle machinery. A pseudogene of this gene is found on chromosome 4. Alternate splicing results in multiple transcript variants.[provided by RefSeq, Nov 2010]

CCNH 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=0.00859797).

BP6

Variant 5-87379775-C-A is Benign according to our data. Variant chr5-87379775-C-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 239411.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000644 (98/152256) while in subpopulation EAS AF = 0.0114 (59/5188). AF 95% confidence interval is 0.00905. There are 0 homozygotes in GnomAd4. There are 41 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 98 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RASA1	NM_002890.3 link	c.2528C>A	p.Thr843Asn	missense_variant	Exon 19 of 25	ENST00000274376.11	NP_002881.1	P20936-1Q59GK3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RASA1	ENST00000274376.11 link	c.2528C>A	p.Thr843Asn	missense_variant	Exon 19 of 25	1	NM_002890.3	ENSP00000274376.6		P20936-1

Frequencies

GnomAD3 genomes

AF:

0.000644

AC:

AN:

152138

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000386

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00111

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0113

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00144

GnomAD2 exomes

AF:

0.00137

AC:

344

AN:

250278

AF XY:

0.00115

show subpopulations

Gnomad AFR exome

AF:

0.000617

Gnomad AMR exome

AF:

0.00223

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0130

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000354

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.000437

AC:

638

AN:

1460428

Hom.:

Cov.:

AF XY:

0.000423

AC XY:

307

AN XY:

726526

show subpopulations

African (AFR)

AF:

0.000449

AC:

AN:

33414

American (AMR)

AF:

0.00204

AC:

AN:

44676

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26072

East Asian (EAS)

AF:

0.0112

AC:

443

AN:

39512

South Asian (SAS)

AF:

0.000220

AC:

AN:

86194

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53390

Middle Eastern (MID)

AF:

0.000174

AC:

AN:

5742

European-Non Finnish (NFE)

AF:

0.00000630

AC:

AN:

1111106

Other (OTH)

AF:

0.00103

AC:

AN:

60322

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

121

151

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.000644

AC:

AN:

152256

Hom.:

Cov.:

AF XY:

0.000551

AC XY:

AN XY:

74456

show subpopulations

African (AFR)

AF:

0.000385

AC:

AN:

41562

American (AMR)

AF:

0.00111

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.0114

AC:

AN:

5188

South Asian (SAS)

AF:

0.000208

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10604

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68004

Other (OTH)

AF:

0.00142

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.516

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000716

Hom.:

Bravo

AF:

0.00102

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00133

AC:

161

Asia WGS

AF:

0.00751

AC:

AN:

3474

EpiCase

AF:

0.0000546

EpiControl

AF:

0.00

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Apr 15, 2024

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

See Variant Classification Assertion Criteria. -

Sep 17, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Parkes Weber syndrome

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Capillary malformation-arteriovenous malformation syndrome

Benign:1

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiovascular phenotype

Benign:1

Dec 04, 2018

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

RASA1-related disorder

Benign:1

Mar 11, 2020

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.56

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.41

T;.;.;.

Eigen

Benign

0.020

Eigen_PC

Benign

0.20

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.94

D;D;D;D

MetaRNN

Benign

0.0086

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.72

N;.;.;.

PhyloP100

5.5

PrimateAI

Uncertain

0.61

PROVEAN

Benign

-0.60

N;N;N;N

REVEL

Benign

0.062

Sift

Benign

0.17

T;T;T;T

Sift4G

Benign

0.49

T;T;T;T

Polyphen

0.0030

B;B;.;B

Vest4

0.38

MVP

0.31

MPC

0.86

ClinPred

0.012

GERP RS

5.0

Varity_R

0.32

gMVP

0.35

Mutation Taster

=88/12

polymorphism

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over