19-15453308-C-T

Variant names:

• chr19-15453308-C-T
• rs371535313
• NM_022904.3:c.2469G>A
• RASAL3 p.Arg823Arg

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_022904.3(RASAL3):​c.2469G>A​(p.Arg823Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000175 in 1,489,314 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: RASAL3 NM_022904.3 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.335
• 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 -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP7: Synonymous conserved (PhyloP=0.335 with no splicing effect.

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.2469G>A	p.Arg823Arg	synonymous	Exon 15 of 18	NP_075055.1	Q86YV0-1
	RASAL3	NM_001400377.1		c.2478G>A	p.Arg826Arg	synonymous	Exon 15 of 18	NP_001387306.1
	RASAL3	NM_001400378.1		c.2451G>A	p.Arg817Arg	synonymous	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.2469G>A	p.Arg823Arg	synonymous	Exon 15 of 18	ENSP00000341905.5	Q86YV0-1
	RASAL3	ENST00000909962.1		c.2496G>A	p.Arg832Arg	synonymous	Exon 15 of 18	ENSP00000580021.1
	RASAL3	ENST00000909960.1		c.2478G>A	p.Arg826Arg	synonymous	Exon 15 of 18	ENSP00000580019.1

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152030 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.0000112 AC: 1 AN: 89374 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.0000127 AC: 17 AN: 1337174 Hom.: 0 Cov.: 32 AF XY: 0.00000762 AC XY: 5 AN XY: 656020

African (AFR) AF: 0.00 AC: 0 AN: 29230

American (AMR) AF: 0.00 AC: 0 AN: 26952

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21062

East Asian (EAS) AF: 0.0000288 AC: 1 AN: 34758

South Asian (SAS) AF: 0.00 AC: 0 AN: 70536

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38576

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4362

European-Non Finnish (NFE) AF: 0.00000189 AC: 2 AN: 1056210

Other (OTH) AF: 0.000252 AC: 14 AN: 55488

GnomAD4 genome AF: 0.0000592 AC: 9 AN: 152140 Hom.: 0 Cov.: 32 AF XY: 0.0000672 AC XY: 5 AN XY: 74386

African (AFR) AF: 0.000120 AC: 5 AN: 41552

American (AMR) AF: 0.0000654 AC: 1 AN: 15286

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

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5158

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10550

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67976

Other (OTH) AF: 0.000947 AC: 2 AN: 2112

Alfa AF: 0.000142 Hom.: 0

Bravo AF: 0.0000264

Asia WGS AF: 0.00608 AC: 21 AN: 3466

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	6.8
DANN	Benign	0.91
PhyloP100		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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs371535313;

hg19: chr19-15564119;