3-141487096-G-C

Position:

• chr3-141487096-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_006506.5(RASA2):​c.13G>C​(p.Ala5Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000813 in 1,230,214 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A5G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000081 (0 hom.)
• Consequence: RASA2 NM_006506.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.126

Genes affected

RASA2 (HGNC:9872): (RAS p21 protein activator 2) The protein encoded by this gene is member of the GAP1 family of GTPase-activating proteins. The gene product stimulates the GTPase activity of normal RAS p21 but not its oncogenic counterpart. Acting as a suppressor of RAS function, the protein enhances the weak intrinsic GTPase activity of RAS proteins resulting in the inactive GDP-bound form of RAS, thereby allowing control of cellular proliferation and differentiation. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2014]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.23272684).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RASA2	NM_006506.5	c.13G>C	p.Ala5Pro	missense_variant	1/24	ENST00000286364.9
RASA2	NM_001303246.3	c.13G>C	p.Ala5Pro	missense_variant	1/25
RASA2	NM_001303245.3	c.13G>C	p.Ala5Pro	missense_variant	1/24
RASA2	XM_047448652.1	c.13G>C	p.Ala5Pro	missense_variant	1/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RASA2	ENST00000286364.9	c.13G>C	p.Ala5Pro	missense_variant	1/24	1	NM_006506.5	P1
RASA2	ENST00000515549.1	c.13G>C	p.Ala5Pro	missense_variant, NMD_transcript_variant	1/5	4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000813 AC: 10 AN: 1230214 Hom.: 0 Cov.: 31 AF XY: 0.00000661 AC XY: 4 AN XY: 604980

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: 0.0000101

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 29, 2023

The p.A5P variant (also known as c.13G>C), located in coding exon 1 of the RASA2 gene, results from a G to C substitution at nucleotide position 13. The alanine at codon 5 is replaced by proline, an amino acid with highly similar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.070	D
BayesDel_noAF	Benign	-0.14
CADD	Benign	23
DANN	Uncertain	0.97
Eigen	Benign	-0.0056
Eigen_PC	Benign	-0.073
FATHMM_MKL	Benign	0.49	N
LIST_S2	Benign	0.51	T;T
M_CAP	Pathogenic	0.61	D
MetaRNN	Benign	0.23	T;T
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	0.0	N;.
MutationTaster	Benign	0.96	N;N
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-0.19	N;N
REVEL	Benign	0.19
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.051	T;T
Vest4		0.21
MutPred		0.29		Gain of loop (P = 0.0045);Gain of loop (P = 0.0045);
MVP		0.83
MPC		0.44
ClinPred		0.52	D
GERP RS		1.6
gMVP		0.43

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

LitVar

Other links and lift over

dbSNP: rs1335723224; hg19: chr3-141205938;