Variant 7-102595694-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PP3

The ENST00000262940.12(RASA4):c.946G>A(p.Gly316Arg) variant causes a missense change. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00025 ( 0 hom., cov: 22)

Exomes 𝑓: 0.000018 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

RASA4
ENST00000262940.12 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.30

Variant links:

Genes affected

RASA4 (HGNC:23181): (RAS p21 protein activator 4) This gene encodes a member of the GAP1 family of GTPase-activating proteins that suppresses the Ras/mitogen-activated protein kinase pathway in response to Ca(2+). Stimuli that increase intracellular Ca(2+) levels result in the translocation of this protein to the plasma membrane, where it activates Ras GTPase activity. Consequently, Ras is converted from the active GTP-bound state to the inactive GDP-bound state and no longer activates downstream pathways that regulate gene expression, cell growth, and differentiation. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

RASA4 links:

ENSG00000205236 (HGNC:):

ENSG00000205236 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.798

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RASA4	NM_006989.6 linkuse as main transcript	c.946G>A	p.Gly316Arg	missense_variant	10/21	ENST00000262940.12	NP_008920.5	O43374-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
RASA4	ENST00000262940.12 linkuse as main transcript	c.946G>A	p.Gly316Arg	missense_variant	10/21	1	NM_006989.6	ENSP00000262940.8	O43374-1
ENSG00000205236	ENST00000519541.1 linkuse as main transcript	n.*836G>A		non_coding_transcript_exon_variant	15/26	2		ENSP00000429397.1	A0A286YEE6
ENSG00000205236	ENST00000519541.1 linkuse as main transcript	n.*836G>A		3_prime_UTR_variant	15/26	2		ENSP00000429397.1	A0A286YEE6

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

134328

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.000975

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

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

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000180

AC:

AN:

1001036

Hom.:

Cov.:

AF XY:

0.00000597

AC XY:

AN XY:

502590

show subpopulations

Gnomad4 AFR exome

AF:

0.000725

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.0000228

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000245

AC:

AN:

134432

Hom.:

Cov.:

AF XY:

0.000247

AC XY:

AN XY:

64760

show subpopulations

Gnomad4 AFR

AF:

0.000972

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

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

Aug 02, 2021

The c.946G>A (p.G316R) alteration is located in exon 10 (coding exon 10) of the RASA4 gene. This alteration results from a G to A substitution at nucleotide position 946, causing the glycine (G) at amino acid position 316 to be replaced by an arginine (R). 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

Pathogenic

0.58

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Uncertain

-0.040

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.54

D;T;.;T;.

Eigen

Uncertain

0.53

Eigen_PC

Uncertain

0.46

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.97

D;.;D;D;D

M_CAP

Uncertain

0.17

MetaRNN

Pathogenic

0.80

D;D;D;D;D

MetaSVM

Uncertain

-0.12

MutationAssessor

Uncertain

2.1

M;.;M;.;.

MutationTaster

Benign

1.0

D;D;D;D;D;D

PrimateAI

Pathogenic

0.89

PROVEAN

Pathogenic

-6.1

D;D;D;D;D

REVEL

Uncertain

0.35

Sift

Uncertain

0.0030

D;D;D;D;D

Sift4G

Uncertain

0.0020

D;D;D;D;D

Polyphen

1.0

D;.;D;.;.

Vest4

0.39

MutPred

0.41

Loss of ubiquitination at K312 (P = 0.0384);.;Loss of ubiquitination at K312 (P = 0.0384);.;.;

MVP

0.61

MPC

3.0

ClinPred

0.99

GERP RS

3.6

Varity_R

0.93

gMVP

0.63

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

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