12-113104177-G-A

Position:

• chr12-113104177-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001301202.2(RASAL1):​c.1952C>T​(p.Thr651Ile) 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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: RASAL1 NM_001301202.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.23

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16304976).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RASAL1	NM_001301202.2	c.1952C>T	p.Thr651Ile	missense_variant	17/21	ENST00000548055.2	NP_001288131.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RASAL1	ENST00000548055.2	c.1952C>T	p.Thr651Ile	missense_variant	17/21	1	NM_001301202.2	ENSP00000448510.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 41

GnomAD4 genome Cov.: 33

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

Mar 30, 2024

The c.1955C>T (p.T652I) alteration is located in exon 18 (coding exon 17) of the RASAL1 gene. This alteration results from a C to T substitution at nucleotide position 1955, causing the threonine (T) at amino acid position 652 to be replaced by an isoleucine (I). 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	0.090
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Benign	0.058	.;T;.;.
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.25
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.84	T;T;T;T
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.16	T;T;T;T
MetaSVM	Benign	-0.81	T
MutationAssessor	Uncertain	2.0	.;M;.;.
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.020	N;N;N;N
REVEL	Benign	0.056
Sift	Benign	0.32	T;T;T;T
Sift4G	Benign	0.54	T;T;T;T
Polyphen		0.0050, 0.035	.;B;B;.
Vest4		0.083
MutPred		0.51		.;Loss of disorder (P = 0.1372);.;.;
MVP		0.80
MPC		0.24
ClinPred		0.14	T
GERP RS		1.2
Varity_R		0.053
gMVP		0.26

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

Other links and lift over

dbSNP: rs964138813; hg19: chr12-113541982;