Genetic Variant RASAL3:p.Asp1009Glu (chr19-15451804-G-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.3027C>A(p.Asp1009Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000132 in 1,596,108 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000013 ( 0 hom. )

Consequence

RASAL3
NM_022904.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.462

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:

Genome browser will be placed here

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=0.1070784).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RASAL3	NM_022904.3 link	c.3027C>A	p.Asp1009Glu	missense_variant	Exon 18 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.3027C>A	p.Asp1009Glu	missense_variant	Exon 18 of 18	2	NM_022904.3	ENSP00000341905.5	Q86YV0-1
RASAL3	ENST00000599694.1 link	c.1326C>A	p.Asp442Glu	missense_variant	Exon 7 of 7	5		ENSP00000468841.1	M0QX12
RASAL3	ENST00000609274 link	c.*850C>A		3_prime_UTR_variant	Exon 4 of 4	2		ENSP00000476634.1	V9GYD1
RASAL3	ENST00000602101.6 link	n.4098C>A		non_coding_transcript_exon_variant	Exon 16 of 16	2

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000162

AC:

AN:

246940

Hom.:

AF XY:

0.0000299

AC XY:

AN XY:

133970

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000292

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:

0.0000268

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000132

AC:

AN:

1443920

Hom.:

Cov.:

AF XY:

0.0000112

AC XY:

AN XY:

714684

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000451

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:

0.0000127

Gnomad4 OTH exome

AF:

0.0000505

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152188

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74336

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000654

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

Bravo

AF:

0.00000756

ExAC

AF:

0.00000826

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 24, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3027C>A (p.D1009E) alteration is located in exon 18 (coding exon 17) of the RASAL3 gene. This alteration results from a C to A substitution at nucleotide position 3027, causing the aspartic acid (D) at amino acid position 1009 to be replaced by a glutamic acid (E). 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

0.16

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.67

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0037

Eigen

Benign

-0.42

Eigen_PC

Benign

-0.35

FATHMM_MKL

Benign

0.36

LIST_S2

Benign

0.46

M_CAP

Benign

0.014

MetaRNN

Benign

0.11

MetaSVM

Benign

-1.0

MutationAssessor

Benign

2.0

PrimateAI

Benign

0.47

PROVEAN

Benign

-0.34

REVEL

Benign

0.10

Sift

Uncertain

0.0040

Sift4G

Pathogenic

0.0

Polyphen

0.28

Vest4

0.18

MutPred

0.066

Loss of glycosylation at T1010 (P = 0.159);

MVP

0.42

MPC

0.021

ClinPred

0.40

GERP RS

0.46

Varity_R

0.089

gMVP

0.11

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