Genetic Variant NM_022904.3:c.2999C>A (chr19-15451832-G-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_022904.3(RASAL3):c.2999C>A(p.Pro1000His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000825 in 1,453,840 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P1000L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000083 ( 0 hom. )

Consequence

RASAL3
NM_022904.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.66

Publications

2 publications found

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 was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.07411796).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022904.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RASAL3	NM_022904.3	MANE Select	c.2999C>A	p.Pro1000His	missense	Exon 18 of 18	NP_075055.1	Q86YV0-1
RASAL3	NM_001400377.1		c.3008C>A	p.Pro1003His	missense	Exon 18 of 18	NP_001387306.1
RASAL3	NM_001400378.1		c.2981C>A	p.Pro994His	missense	Exon 18 of 18	NP_001387307.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RASAL3	ENST00000343625.12	TSL:2 MANE Select	c.2999C>A	p.Pro1000His	missense	Exon 18 of 18	ENSP00000341905.5	Q86YV0-1
RASAL3	ENST00000909962.1		c.3026C>A	p.Pro1009His	missense	Exon 18 of 18	ENSP00000580021.1
RASAL3	ENST00000909960.1		c.3008C>A	p.Pro1003His	missense	Exon 18 of 18	ENSP00000580019.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000402

AC:

AN:

248702

AF XY:

0.00000741

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000887

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000825

AC:

AN:

1453840

Hom.:

Cov.:

AF XY:

0.0000125

AC XY:

AN XY:

721570

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33360

American (AMR)

AF:

0.00

AC:

AN:

44584

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26058

East Asian (EAS)

AF:

0.00

AC:

AN:

39452

South Asian (SAS)

AF:

0.00

AC:

AN:

86038

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53210

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4906

European-Non Finnish (NFE)

AF:

0.00000904

AC:

AN:

1106306

Other (OTH)

AF:

0.0000334

AC:

AN:

59926

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000827

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.086

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.59

CADD

Benign

(source)

DANN

Benign

0.89

DEOGEN2

Benign

0.010

Eigen

Benign

-0.89

Eigen_PC

Benign

-0.81

FATHMM_MKL

Benign

0.20

LIST_S2

Benign

0.42

M_CAP

Benign

0.012

MetaRNN

Benign

0.074

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.2

PhyloP100

2.7

PrimateAI

Benign

0.30

PROVEAN

Benign

-2.1

REVEL

Benign

0.032

Sift

Benign

0.064

Sift4G

Uncertain

0.0020

Polyphen

0.0

Vest4

0.22

MutPred

0.22

Loss of glycosylation at P1000 (P = 0.0513)

MVP

0.17

MPC

0.010

ClinPred

0.062

GERP RS

2.0

Varity_R

0.070

gMVP

0.22

Mutation Taster

=96/4

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over