Genetic Variant RASAL3:p.Arg824His (chr19-15453306-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_022904.3(RASAL3):c.2471G>A(p.Arg824His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000149 in 1,338,302 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000015 ( 0 hom. )

Consequence

RASAL3
NM_022904.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.19

Variant links:

Genes affected

RASAL3 (HGNC:26129): (RAS protein activator like 3) This gene belongs to the Ras GTPase-activating proteins (RasGAP) family and encodes a protein with pleckstrin homology (PH), C2, and Ras GTPase-activation protein (RasGAP) domains. This protein is localized near or at the plasma membrane when expressed exogenously. Reduced expression of this gene in some cell lines resulted in increased levels of the active form of Ras (Ras-GTP), suggesting that this gene may play a role in negatively regulating the Ras signaling pathway. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jan 2017]

RASAL3 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.22724938).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RASAL3	NM_022904.3 link	c.2471G>A	p.Arg824His	missense_variant	Exon 15 of 18	ENST00000343625.12	NP_075055.1	Q86YV0-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
RASAL3	ENST00000343625.12 link	c.2471G>A	p.Arg824His	missense_variant	Exon 15 of 18	2	NM_022904.3	ENSP00000341905.5	Q86YV0-1
RASAL3	ENST00000599694.1 link	c.992G>A	p.Arg331His	missense_variant	Exon 6 of 7	5		ENSP00000468841.1	M0QX12
RASAL3	ENST00000609274.5 link	c.326G>A	p.Arg109His	missense_variant	Exon 3 of 4	2		ENSP00000476634.1	V9GYD1
RASAL3	ENST00000602101.6 link	n.2993G>A		non_coding_transcript_exon_variant	Exon 14 of 16	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000110

AC:

AN:

90900

Hom.:

AF XY:

0.0000204

AC XY:

AN XY:

48976

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.0000289

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000149

AC:

AN:

1338302

Hom.:

Cov.:

AF XY:

0.00000305

AC XY:

AN XY:

656744

show subpopulations

Gnomad4 AFR exome

AF:

0.00

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:

0.00000189

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 14, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2471G>A (p.R824H) alteration is located in exon 15 (coding exon 14) of the RASAL3 gene. This alteration results from a G to A substitution at nucleotide position 2471, causing the arginine (R) at amino acid position 824 to be replaced by a histidine (H). 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

0.11

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.50

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.097

T;T

Eigen

Benign

-0.12

Eigen_PC

Benign

-0.29

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.80

T;T

M_CAP

Uncertain

0.21

MetaRNN

Benign

0.23

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.3

.;M

PrimateAI

Pathogenic

0.87

PROVEAN

Benign

0.060

.;N

REVEL

Benign

0.044

Sift

Uncertain

0.0090

.;D

Sift4G

Uncertain

0.011

D;D

Polyphen

0.99

.;D

Vest4

0.16

MutPred

0.44

.;Loss of methylation at R824 (P = 0.0496);

MVP

0.50

MPC

1.9

ClinPred

0.77

GERP RS

3.0

Varity_R

0.063

gMVP

0.20

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