Variant chr7-102595639-C-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The ENST00000262940.12(RASA4):c.1001G>T(p.Arg334Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R334P) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00089 ( 0 hom., cov: 21)

Exomes 𝑓: 0.000087 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

RASA4
ENST00000262940.12 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.813

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 Likely_benign. Variant got -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.2064246).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RASA4	NM_006989.6 linkuse as main transcript	c.1001G>T	p.Arg334Leu	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.1001G>T	p.Arg334Leu	missense_variant	10/21	1	NM_006989.6	ENSP00000262940.8	O43374-1
ENSG00000205236	ENST00000519541.1 linkuse as main transcript	n.*891G>T		non_coding_transcript_exon_variant	15/26	2		ENSP00000429397.1	A0A286YEE6
ENSG00000205236	ENST00000519541.1 linkuse as main transcript	n.*891G>T		3_prime_UTR_variant	15/26	2		ENSP00000429397.1	A0A286YEE6

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

122

AN:

136326

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.00325

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000521

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:

0.00161

GnomAD3 exomes

AF:

0.000113

AC:

AN:

53078

Hom.:

AF XY:

0.0000746

AC XY:

AN XY:

26810

show subpopulations

Gnomad AFR exome

AF:

0.000974

Gnomad AMR exome

AF:

0.0000973

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

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000872

AC:

AN:

1066812

Hom.:

Cov.:

AF XY:

0.0000639

AC XY:

AN XY:

531716

show subpopulations

Gnomad4 AFR exome

AF:

0.00365

Gnomad4 AMR exome

AF:

0.000190

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:

0.00000124

Gnomad4 OTH exome

AF:

0.000130

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000894

AC:

122

AN:

136432

Hom.:

Cov.:

AF XY:

0.000894

AC XY:

AN XY:

65962

show subpopulations

Gnomad4 AFR

AF:

0.00324

Gnomad4 AMR

AF:

0.000520

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:

0.00159

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

Jan 04, 2024

The c.1001G>T (p.R334L) alteration is located in exon 10 (coding exon 10) of the RASA4 gene. This alteration results from a G to T substitution at nucleotide position 1001, causing the arginine (R) at amino acid position 334 to be replaced by a leucine (L). 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

0.27

BayesDel_addAF

Uncertain

0.021

BayesDel_noAF

Benign

-0.21

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.67

D;D;.;D

Eigen

Benign

-0.12

Eigen_PC

Benign

-0.18

FATHMM_MKL

Benign

0.34

LIST_S2

Uncertain

0.91

D;.;D;D

M_CAP

Uncertain

0.24

MetaRNN

Benign

0.21

T;T;T;T

MetaSVM

Uncertain

0.036

MutationAssessor

Benign

1.3

L;.;L;.

MutationTaster

Benign

1.0

D;D;D;D;D;D

PrimateAI

Uncertain

0.69

PROVEAN

Pathogenic

-4.8

D;D;D;D

REVEL

Uncertain

0.44

Sift

Uncertain

0.017

D;D;D;D

Sift4G

Uncertain

0.059

T;T;T;T

Polyphen

0.91

P;.;P;.

Vest4

0.35

MVP

0.55

MPC

2.8

ClinPred

0.17

GERP RS

3.6

Varity_R

0.55

gMVP

0.37

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