19-15453228-G-C

Variant names:

• chr19-15453228-G-C
• rs1298691412
• NM_022904.3:c.2549C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_022904.3(RASAL3):​c.2549C>G​(p.Ala850Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000691 in 1,447,572 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 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. A850V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: RASAL3 NM_022904.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0700
• 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 -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.03715989).

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.2549C>G	p.Ala850Gly	missense	Exon 15 of 18	NP_075055.1	Q86YV0-1
	RASAL3	NM_001400377.1		c.2558C>G	p.Ala853Gly	missense	Exon 15 of 18	NP_001387306.1
	RASAL3	NM_001400378.1		c.2531C>G	p.Ala844Gly	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.2549C>G	p.Ala850Gly	missense	Exon 15 of 18	ENSP00000341905.5	Q86YV0-1
	RASAL3	ENST00000909962.1		c.2576C>G	p.Ala859Gly	missense	Exon 15 of 18	ENSP00000580021.1
	RASAL3	ENST00000909960.1		c.2558C>G	p.Ala853Gly	missense	Exon 15 of 18	ENSP00000580019.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.91e-7 AC: 1 AN: 1447572 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 719400

African (AFR) AF: 0.00 AC: 0 AN: 33168

American (AMR) AF: 0.00 AC: 0 AN: 43026

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25832

East Asian (EAS) AF: 0.00 AC: 0 AN: 39074

South Asian (SAS) AF: 0.00 AC: 0 AN: 84536

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50030

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5690

European-Non Finnish (NFE) AF: 9.04e-7 AC: 1 AN: 1106374

Other (OTH) AF: 0.00 AC: 0 AN: 59842

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.051
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.80
CADD	Benign	2.8
DANN	Benign	0.78
DEOGEN2	Benign	0.0037	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.89
FATHMM_MKL	Benign	0.0025	N
LIST_S2	Benign	0.43	T
M_CAP	Benign	0.069	D
MetaRNN	Benign	0.037	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-1.4	N
PhyloP100		-0.070
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	0.19	N
REVEL	Benign	0.040
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.042
MutPred		0.31		Loss of stability (P = 0.0383)
MVP		0.072
MPC		0.82
ClinPred		0.030	T
GERP RS		3.5
Varity_R		0.035
gMVP		0.28
Mutation Taster		=97/3	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: rs1298691412; hg19: chr19-15564039;