Genetic Variant RASAL1:p.Glu756Lys (chr12-113100640-C-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_001301202.2(RASAL1):c.2266G>A(p.Glu756Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict 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. E756Q) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Consequence

RASAL1
NM_001301202.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.51

Publications

0 publications found

Variant links:

Genes affected

RASAL1 (HGNC:9873): (RAS protein activator like 1) The protein encoded by this gene is member of the GAP1 family of GTPase-activating proteins. These proteins stimulate the GTPase activity of normal RAS p21 but not its oncogenic counterpart. Acting as a suppressor of RAS function, the protein enhances the weak intrinsic GTPase activity of RAS proteins resulting in the inactive GDP-bound form of RAS, thereby allowing control of cellular proliferation and differentiation. This particular family member contains domains which are characteristic of the GAP1 subfamily of RasGAP proteins but, in contrast to the other GAP1 family members, this protein is strongly and selectively expressed in endocrine tissues. Alternatively spliced transcript variants that encode different isoforms have been described [provided by RefSeq, Jul 2010]

RASAL1 Gene-Disease associations (from GenCC):

breast cancer
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

RASAL1 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=0.13011232).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001301202.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RASAL1	NM_001301202.2	MANE Select	c.2266G>A	p.Glu756Lys	missense	Exon 20 of 21	NP_001288131.1	O95294-4
RASAL1	NM_001193520.2		c.2269G>A	p.Glu757Lys	missense	Exon 21 of 22	NP_001180449.1	O95294-3
RASAL1	NM_001394081.1		c.2269G>A	p.Glu757Lys	missense	Exon 20 of 21	NP_001381010.1	O95294-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RASAL1	ENST00000548055.2	TSL:1 MANE Select	c.2266G>A	p.Glu756Lys	missense	Exon 20 of 21	ENSP00000448510.1	O95294-4
RASAL1	ENST00000546530.5	TSL:1	c.2269G>A	p.Glu757Lys	missense	Exon 21 of 22	ENSP00000450244.1	O95294-3
RASAL1	ENST00000261729.9	TSL:1	c.2263G>A	p.Glu755Lys	missense	Exon 21 of 22	ENSP00000261729.5	O95294-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.092

BayesDel_addAF

Benign

-0.065

BayesDel_noAF

Benign

-0.33

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.0053

Eigen

Benign

-0.63

Eigen_PC

Benign

-0.62

FATHMM_MKL

Benign

0.10

LIST_S2

Benign

0.76

M_CAP

Benign

0.024

MetaRNN

Benign

0.13

MetaSVM

Benign

-0.84

MutationAssessor

Uncertain

2.8

PhyloP100

1.5

PrimateAI

Benign

0.45

PROVEAN

Benign

-1.0

REVEL

Benign

0.17

Sift

Benign

0.36

Sift4G

Benign

0.31

Polyphen

0.057

Vest4

0.15

MutPred

0.33

Gain of ubiquitination at E755 (P = 0.006)

MVP

0.78

MPC

0.25

ClinPred

0.20

GERP RS

4.1

Varity_R

0.14

gMVP

0.24

Mutation Taster

=95/5

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over