Variant 13-113992509-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_007368.4(RASA3):c.2221A>G(p.Met741Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000103 in 1,461,118 control chromosomes in the GnomAD database, with no homozygous occurrence. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 0.000010 ( 0 hom. )

Consequence

RASA3
NM_007368.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.25

Variant links:

Genes affected

RASA3 (HGNC:20331): (RAS p21 protein activator 3) This gene encodes a protein that binds inositol 1,3,4,5-tetrakisphosphate and stimulates the GTPase activity of Ras p21. This protein functions as a negative regulator of the Ras signalling pathway. It is localized to the cell membrane via a pleckstrin homology (PH) domain in the C-terminal region. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2016]

RASA3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RASA3	NM_007368.4 link	c.2221A>G	p.Met741Val	missense_variant	22/24	ENST00000334062.8	NP_031394.2	Q14644-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RASA3	ENST00000334062.8 link	c.2221A>G	p.Met741Val	missense_variant	22/24	1	NM_007368.4	ENSP00000335029.7		Q14644-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000798

AC:

AN:

250566

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135780

show subpopulations

Gnomad AFR exome

AF:

0.0000618

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000103

AC:

AN:

1461118

Hom.:

Cov.:

AF XY:

0.00000826

AC XY:

AN XY:

726820

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000126

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000630

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 01, 2023

The c.2221A>G (p.M741V) alteration is located in exon 22 (coding exon 22) of the RASA3 gene. This alteration results from a A to G substitution at nucleotide position 2221, causing the methionine (M) at amino acid position 741 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.030

BayesDel_noAF

Benign

-0.10

CADD

Benign

DANN

Benign

0.90

DEOGEN2

Uncertain

0.43

Eigen

Benign

-0.29

Eigen_PC

Benign

-0.18

FATHMM_MKL

Uncertain

0.94

M_CAP

Benign

0.063

MetaRNN

Uncertain

0.60

MetaSVM

Benign

-0.46

MutationAssessor

Benign

1.3

PrimateAI

Uncertain

0.56

PROVEAN

Benign

-1.7

REVEL

Uncertain

0.46

Sift

Benign

0.17

Sift4G

Benign

0.20

Polyphen

0.0

Vest4

0.67

MutPred

0.47

Loss of ubiquitination at K743 (P = 0.0853);

MVP

0.79

MPC

0.39

ClinPred

0.063

GERP RS

3.8

Varity_R

0.28

gMVP

0.76

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.15

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