Genetic Variant RASAL1:p.Gly704Arg (chr12-113102004-C-G) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_001301202.2(RASAL1):c.2110G>C(p.Gly704Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,460,996 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

RASAL1
NM_001301202.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.45

Publications

2 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: Likely_pathogenic. The variant received 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.977

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.2110G>C	p.Gly704Arg	missense	Exon 19 of 21	NP_001288131.1	O95294-4
RASAL1	NM_001193520.2		c.2113G>C	p.Gly705Arg	missense	Exon 20 of 22	NP_001180449.1	O95294-3
RASAL1	NM_001394081.1		c.2113G>C	p.Gly705Arg	missense	Exon 19 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.2110G>C	p.Gly704Arg	missense	Exon 19 of 21	ENSP00000448510.1	O95294-4
RASAL1	ENST00000546530.5	TSL:1	c.2113G>C	p.Gly705Arg	missense	Exon 20 of 22	ENSP00000450244.1	O95294-3
RASAL1	ENST00000261729.9	TSL:1	c.2107G>C	p.Gly703Arg	missense	Exon 20 of 22	ENSP00000261729.5	O95294-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1460996

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726812

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33462

American (AMR)

AF:

0.00

AC:

AN:

44550

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26058

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39680

South Asian (SAS)

AF:

0.00

AC:

AN:

86152

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53308

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5750

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111692

Other (OTH)

AF:

0.00

AC:

AN:

60344

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

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

Pathogenic

0.91

BayesDel_addAF

Pathogenic

0.53

BayesDel_noAF

Pathogenic

0.52

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.77

Eigen

Uncertain

0.63

Eigen_PC

Uncertain

0.50

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.93

M_CAP

Pathogenic

0.89

MetaRNN

Pathogenic

0.98

MetaSVM

Pathogenic

0.84

MutationAssessor

Uncertain

2.4

PhyloP100

7.4

PrimateAI

Uncertain

0.79

PROVEAN

Pathogenic

-6.1

REVEL

Pathogenic

0.90

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.017

Polyphen

1.0

Vest4

0.75

MutPred

0.74

Gain of MoRF binding (P = 0.0064)

MVP

0.98

MPC

0.91

ClinPred

1.0

GERP RS

5.1

Varity_R

0.77

gMVP

0.74

Mutation Taster

=73/27

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