19-15453298-G-T

Variant names:

• chr19-15453298-G-T
• rs761344879
• NM_022904.3:c.2479C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_022904.3(RASAL3):​c.2479C>A​(p.Arg827Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000741 in 1,348,746 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R827C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.4e-7 (0 hom.)
• Consequence: RASAL3 NM_022904.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.87
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18452021).

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.2479C>A	p.Arg827Ser	missense	Exon 15 of 18	NP_075055.1	Q86YV0-1
	RASAL3	NM_001400377.1		c.2488C>A	p.Arg830Ser	missense	Exon 15 of 18	NP_001387306.1
	RASAL3	NM_001400378.1		c.2461C>A	p.Arg821Ser	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.2479C>A	p.Arg827Ser	missense	Exon 15 of 18	ENSP00000341905.5	Q86YV0-1
	RASAL3	ENST00000909962.1		c.2506C>A	p.Arg836Ser	missense	Exon 15 of 18	ENSP00000580021.1
	RASAL3	ENST00000909960.1		c.2488C>A	p.Arg830Ser	missense	Exon 15 of 18	ENSP00000580019.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.41e-7 AC: 1 AN: 1348746 Hom.: 0 Cov.: 32 AF XY: 0.00000151 AC XY: 1 AN XY: 662786

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 29620

American (AMR) AF: 0.00 AC: 0 AN: 28284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21838

East Asian (EAS) AF: 0.0000286 AC: 1 AN: 34980

South Asian (SAS) AF: 0.00 AC: 0 AN: 72642

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4650

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1061160

Other (OTH) AF: 0.00 AC: 0 AN: 55946

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	19
DANN	Benign	0.92
DEOGEN2	Benign	0.033	T
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.40
FATHMM_MKL	Benign	0.40	N
LIST_S2	Benign	0.57	T
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L
PhyloP100		1.9
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	0.23	N
REVEL	Benign	0.049
Sift	Uncertain	0.0030	D
Sift4G	Benign	0.27	T
Polyphen		0.072	B
Vest4		0.26
MutPred		0.35		Gain of phosphorylation at R827 (P = 0.0015)
MVP		0.29
MPC		0.94
ClinPred		0.23	T
GERP RS		3.1
Varity_R		0.12
gMVP		0.24
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs761344879; hg19: chr19-15564109;