chr3-141487094-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4BS2

The NM_006506.5(RASA2):c.11C>T(p.Ala4Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000153 in 1,374,532 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. A4A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000040 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

RASA2
NM_006506.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 0.929

Publications

0 publications found

Variant links:

Genes affected

RASA2 (HGNC:9872): (RAS p21 protein activator 2) The protein encoded by this gene is member 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. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2014]

RASA2 Gene-Disease associations (from GenCC):

Noonan syndrome
Inheritance: AD Classification: SUPPORTIVE, LIMITED Submitted by: ClinGen, Orphanet
cardiofaciocutaneous syndrome
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
Costello 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

RASA2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.34783757).

BS2

High AC in GnomAd4 at 6 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006506.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RASA2	NM_006506.5	MANE Select	c.11C>T	p.Ala4Val	missense	Exon 1 of 24	NP_006497.2
RASA2	NM_001303246.3		c.11C>T	p.Ala4Val	missense	Exon 1 of 25	NP_001290175.1
RASA2	NM_001303245.3		c.11C>T	p.Ala4Val	missense	Exon 1 of 24	NP_001290174.1	Q15283-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RASA2	ENST00000286364.9	TSL:1 MANE Select	c.11C>T	p.Ala4Val	missense	Exon 1 of 24	ENSP00000286364.3	Q15283-2
RASA2	ENST00000930693.1		c.11C>T	p.Ala4Val	missense	Exon 1 of 25	ENSP00000600752.1
RASA2	ENST00000950127.1		c.11C>T	p.Ala4Val	missense	Exon 1 of 25	ENSP00000620186.1

Frequencies

GnomAD3 genomes

AF:

0.0000399

AC:

AN:

150454

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000970

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000662

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000194

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

GnomAD4 exome

AF:

0.0000123

AC:

AN:

1224078

Hom.:

Cov.:

AF XY:

0.00000997

AC XY:

AN XY:

601536

show subpopulations

African (AFR)

AF:

0.000288

AC:

AN:

24338

American (AMR)

AF:

0.00

AC:

AN:

18666

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18114

East Asian (EAS)

AF:

0.00

AC:

AN:

24584

South Asian (SAS)

AF:

0.0000164

AC:

AN:

61018

European-Finnish (FIN)

AF:

0.00

AC:

AN:

42720

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3378

European-Non Finnish (NFE)

AF:

0.00000712

AC:

AN:

983452

Other (OTH)

AF:

0.00

AC:

AN:

47808

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.512

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.0000399

AC:

AN:

150454

Hom.:

Cov.:

AF XY:

0.0000545

AC XY:

AN XY:

73418

show subpopulations

African (AFR)

AF:

0.0000970

AC:

AN:

41242

American (AMR)

AF:

0.0000662

AC:

AN:

15114

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3446

East Asian (EAS)

AF:

0.000194

AC:

AN:

5154

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9900

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67474

Other (OTH)

AF:

0.00

AC:

AN:

2066

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

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:

0.0000712

Hom.:

Bravo

AF:

0.0000567

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.43

BayesDel_addAF

Uncertain

0.037

BayesDel_noAF

Benign

-0.18

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.23

Eigen

Benign

0.014

Eigen_PC

Benign

0.025

FATHMM_MKL

Benign

0.65

LIST_S2

Benign

0.60

M_CAP

Pathogenic

0.91

MetaRNN

Benign

0.35

MetaSVM

Benign

-0.77

MutationAssessor

Benign

0.0

PhyloP100

0.93

PrimateAI

Pathogenic

0.84

PROVEAN

Benign

-0.29

REVEL

Benign

0.18

Sift

Benign

0.032

Sift4G

Uncertain

0.045

Vest4

0.35

MutPred

0.32

Gain of catalytic residue at A4 (P = 0.0127)

MVP

0.78

MPC

0.34

ClinPred

0.60

GERP RS

3.0

PromoterAI

0.058

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.0

gMVP

0.36

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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