12-113104048-A-C

Position:

• chr12-113104048-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001301202.2(RASAL1):​c.2002T>G​(p.Leu668Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RASAL1 NM_001301202.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.874

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RASAL1	NM_001301202.2	c.2002T>G	p.Leu668Val	missense_variant	18/21	ENST00000548055.2	NP_001288131.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RASAL1	ENST00000548055.2	c.2002T>G	p.Leu668Val	missense_variant	18/21	1	NM_001301202.2	ENSP00000448510.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 01, 2022

The c.2005T>G (p.L669V) alteration is located in exon 19 (coding exon 18) of the RASAL1 gene. This alteration results from a T to G substitution at nucleotide position 2005, causing the leucine (L) at amino acid position 669 to be replaced by a valine (V). 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	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.36	.;T;.;.
Eigen	Benign	0.072
Eigen_PC	Benign	0.037
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.87	D;D;D;D
M_CAP	Pathogenic	0.44	D
MetaRNN	Uncertain	0.46	T;T;T;T
MetaSVM	Pathogenic	0.85	D
MutationAssessor	Pathogenic	3.0	.;M;.;.
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-1.7	N;N;N;N
REVEL	Uncertain	0.61
Sift	Uncertain	0.0040	D;D;D;D
Sift4G	Uncertain	0.012	D;D;D;D
Polyphen		0.97, 0.88	.;D;P;.
Vest4		0.41
MutPred		0.55		.;Loss of stability (P = 0.0572);.;.;
MVP		0.92
MPC		0.25
ClinPred		0.82	D
GERP RS		2.5
Varity_R		0.22
gMVP		0.37

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-113541853;