19-15453310-G-A

Variant names:

• chr19-15453310-G-A
• rs1040815750
• NM_022904.3:c.2467C>T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_022904.3(RASAL3):​c.2467C>T​(p.Arg823Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000039 in 1,485,384 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00017 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000024 (0 hom.)
• Consequence: RASAL3 NM_022904.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0810

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06314668).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RASAL3	NM_022904.3	c.2467C>T	p.Arg823Trp	missense_variant	Exon 15 of 18	ENST00000343625.12	NP_075055.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RASAL3	ENST00000343625.12	c.2467C>T	p.Arg823Trp	missense_variant	Exon 15 of 18	2	NM_022904.3	ENSP00000341905.5
RASAL3	ENST00000599694.1	c.988C>T	p.Arg330Trp	missense_variant	Exon 6 of 7	5		ENSP00000468841.1
RASAL3	ENST00000609274.5	c.322C>T	p.Arg108Trp	missense_variant	Exon 3 of 4	2		ENSP00000476634.1
RASAL3	ENST00000602101.6	n.2989C>T		non_coding_transcript_exon_variant	Exon 14 of 16	2

Frequencies

GnomAD3 genomes AF: 0.000171 AC: 26 AN: 152004 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000507

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000328

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000117 AC: 10 AN: 85800 Hom.: 0 AF XY: 0.0000867 AC XY: 4 AN XY: 46162

Gnomad AFR exome AF: 0.00160

Gnomad AMR exome AF: 0.000130

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000240 AC: 32 AN: 1333380 Hom.: 0 Cov.: 32 AF XY: 0.0000199 AC XY: 13 AN XY: 653954

Gnomad4 AFR exome AF: 0.000864

Gnomad4 AMR exome AF: 0.000115

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000143

Gnomad4 FIN exome AF: 0.0000260

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000362

GnomAD4 genome AF: 0.000171 AC: 26 AN: 152004 Hom.: 0 Cov.: 32 AF XY: 0.0000943 AC XY: 7 AN XY: 74254

Gnomad4 AFR AF: 0.000507

Gnomad4 AMR AF: 0.000328

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000876 Hom.: 0

Bravo AF: 0.000181

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 30, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2467C>T (p.R823W) alteration is located in exon 15 (coding exon 14) of the RASAL3 gene. This alteration results from a C to T substitution at nucleotide position 2467, causing the arginine (R) at amino acid position 823 to be replaced by a tryptophan (W). 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	0.14
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	16
DANN	Uncertain	0.98
DEOGEN2	Benign	0.077	T;T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.053	N
LIST_S2	Benign	0.80	T;T
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.063	T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.5	.;L
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-2.0	.;N
REVEL	Benign	0.050
Sift	Uncertain	0.018	.;D
Sift4G	Uncertain	0.032	D;D
Polyphen		0.95	.;P
Vest4		0.14
MutPred		0.36		.;Loss of methylation at R824 (P = 0.091);
MVP		0.17
MPC		1.3
ClinPred		0.038	T
GERP RS		-8.0
Varity_R		0.051
gMVP		0.34

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: rs1040815750; hg19: chr19-15564121;