19-15453228-G-C

Variant names:

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

Variant summary

Our verdict is Likely benign. Variant got -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. 14/21 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

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=0.03715989).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RASAL3	NM_022904.3	c.2549C>G	p.Ala850Gly	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.2549C>G	p.Ala850Gly	missense_variant	Exon 15 of 18	2	NM_022904.3	ENSP00000341905.5
RASAL3	ENST00000599694.1	c.1070C>G	p.Ala357Gly	missense_variant	Exon 6 of 7	5		ENSP00000468841.1
RASAL3	ENST00000609274.5	c.404C>G	p.Ala135Gly	missense_variant	Exon 3 of 4	2		ENSP00000476634.1
RASAL3	ENST00000602101.6	n.3071C>G		non_coding_transcript_exon_variant	Exon 14 of 16	2

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.04e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

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;T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.89
FATHMM_MKL	Benign	0.0025	N
LIST_S2	Benign	0.43	T;T
M_CAP	Benign	0.069	D
MetaRNN	Benign	0.037	T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-1.4	.;N
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	0.19	.;N
REVEL	Benign	0.040
Sift	Benign	1.0	.;T
Sift4G	Benign	1.0	T;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

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-15564039;