19-15452727-C-G

Variant names:

• chr19-15452727-C-G
• NM_022904.3:c.2759G>C

Variant summary

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

The NM_022904.3(RASAL3):​c.2759G>C​(p.Arg920Pro) 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: 32)
• Consequence: RASAL3 NM_022904.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.137

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]

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=0.08035728).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RASAL3	NM_022904.3	c.2759G>C	p.Arg920Pro	missense_variant	Exon 16 of 18	ENST00000343625.12	NP_075055.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RASAL3	ENST00000343625.12	c.2759G>C	p.Arg920Pro	missense_variant	Exon 16 of 18	2	NM_022904.3	ENSP00000341905.5
RASAL3	ENST00000609274.5	c.614G>C	p.Arg205Pro	missense_variant	Exon 4 of 4	2		ENSP00000476634.1
RASAL3	ENST00000599694.1	c.1191+380G>C		intron_variant	Intron 6 of 6	5		ENSP00000468841.1
RASAL3	ENST00000602101.6	n.3281G>C		non_coding_transcript_exon_variant	Exon 15 of 16	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 25, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2759G>C (p.R920P) alteration is located in exon 16 (coding exon 15) of the RASAL3 gene. This alteration results from a G to C substitution at nucleotide position 2759, causing the arginine (R) at amino acid position 920 to be replaced by a proline (P). 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	Uncertain	0.36
BayesDel_addAF	Benign	-0.030	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	17
DANN	Benign	0.93
DEOGEN2	Benign	0.12	T;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.095	N
LIST_S2	Benign	0.68	T;T
M_CAP	Uncertain	0.23	D
MetaRNN	Benign	0.080	T;T
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	1.8	.;L
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-1.6	.;N
REVEL	Benign	0.10
Sift	Benign	0.032	.;D
Sift4G	Uncertain	0.023	D;T
Polyphen		0.089	.;B
Vest4		0.62
MutPred		0.27		.;Loss of MoRF binding (P = 0.0033);
MVP		0.29
MPC		1.2
ClinPred		0.089	T
GERP RS		-1.7
Varity_R		0.42
gMVP		0.23

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: chr19-15563538;