NM_022904.3:c.2467C>T

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. 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. 13/22 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
• Publications: 0 publications found

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

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.06314668).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022904.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RASAL3	NM_022904.3	MANE Select	c.2467C>T	p.Arg823Trp	missense	Exon 15 of 18	NP_075055.1	Q86YV0-1
	RASAL3	NM_001400377.1		c.2476C>T	p.Arg826Trp	missense	Exon 15 of 18	NP_001387306.1
	RASAL3	NM_001400378.1		c.2449C>T	p.Arg817Trp	missense	Exon 15 of 18	NP_001387307.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RASAL3	ENST00000343625.12	TSL:2 MANE Select	c.2467C>T	p.Arg823Trp	missense	Exon 15 of 18	ENSP00000341905.5	Q86YV0-1
	RASAL3	ENST00000909962.1		c.2494C>T	p.Arg832Trp	missense	Exon 15 of 18	ENSP00000580021.1
	RASAL3	ENST00000909960.1		c.2476C>T	p.Arg826Trp	missense	Exon 15 of 18	ENSP00000580019.1

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

GnomAD2 exomes AF: 0.000117 AC: 10 AN: 85800 AF XY: 0.0000867

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 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

African (AFR) AF: 0.000864 AC: 25 AN: 28946

American (AMR) AF: 0.000115 AC: 3 AN: 26010

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20846

East Asian (EAS) AF: 0.00 AC: 0 AN: 34642

South Asian (SAS) AF: 0.0000143 AC: 1 AN: 69984

European-Finnish (FIN) AF: 0.0000260 AC: 1 AN: 38522

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1054798

Other (OTH) AF: 0.0000362 AC: 2 AN: 55318

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

African (AFR) AF: 0.000507 AC: 21 AN: 41424

American (AMR) AF: 0.000328 AC: 5 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10548

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67974

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.0000876 Hom.: 0

Bravo AF: 0.000181

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.053	N
LIST_S2	Benign	0.80	T
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.063	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.5	L
PhyloP100		-0.081
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.050
Sift	Uncertain	0.018	D
Sift4G	Uncertain	0.032	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
Mutation Taster		=98/2	polymorphism

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

Other links and lift over

dbSNP: rs1040815750; hg19: chr19-15564121;