rs1394181436

Variant names:

• chr3-141487097-C-G
• rs1394181436
• NM_006506.5:c.14C>G

Your query was ambiguous. Multiple possible variants found:

• chr3-141487097-C-G
• chr3-141487097-C-T
• chr3-141487097-C-A

Variant summary

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

The NM_006506.5(RASA2):​c.14C>G​(p.Ala5Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000145 in 1,381,086 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 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. A5V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 8.1e-7 (0 hom.)
• Consequence: RASA2 NM_006506.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.276
• Publications: 0 publications found

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]

RASA2 Gene-Disease associations (from GenCC):

• Noonan syndrome

  Inheritance: AD Classification: SUPPORTIVE, LIMITED Submitted by: ClinGen, Orphanet
• cardiofaciocutaneous syndrome

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• Costello syndrome

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• Noonan syndrome with multiple lentigines

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• Noonan syndrome-like disorder with loose anagen hair

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

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=0.17000997).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006506.5. 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
	RASA2	NM_006506.5	MANE Select	c.14C>G	p.Ala5Gly	missense	Exon 1 of 24	NP_006497.2
	RASA2	NM_001303246.3		c.14C>G	p.Ala5Gly	missense	Exon 1 of 25	NP_001290175.1
	RASA2	NM_001303245.3		c.14C>G	p.Ala5Gly	missense	Exon 1 of 24	NP_001290174.1	Q15283-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RASA2	ENST00000286364.9	TSL:1 MANE Select	c.14C>G	p.Ala5Gly	missense	Exon 1 of 24	ENSP00000286364.3	Q15283-2
	RASA2	ENST00000930693.1		c.14C>G	p.Ala5Gly	missense	Exon 1 of 25	ENSP00000600752.1
	RASA2	ENST00000950127.1		c.14C>G	p.Ala5Gly	missense	Exon 1 of 25	ENSP00000620186.1

Frequencies

GnomAD3 genomes AF: 0.00000665 AC: 1 AN: 150438 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000243

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 8.13e-7 AC: 1 AN: 1230648 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 605214

African (AFR) AF: 0.00 AC: 0 AN: 24602

American (AMR) AF: 0.00 AC: 0 AN: 19046

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18434

East Asian (EAS) AF: 0.00 AC: 0 AN: 24932

South Asian (SAS) AF: 0.00 AC: 0 AN: 62006

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 43072

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3416

European-Non Finnish (NFE) AF: 0.00000101 AC: 1 AN: 986976

Other (OTH) AF: 0.00 AC: 0 AN: 48164

GnomAD4 genome AF: 0.00000665 AC: 1 AN: 150438 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 73418

African (AFR) AF: 0.0000243 AC: 1 AN: 41214

American (AMR) AF: 0.00 AC: 0 AN: 15124

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3444

East Asian (EAS) AF: 0.00 AC: 0 AN: 5148

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9906

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67480

Other (OTH) AF: 0.00 AC: 0 AN: 2064

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.042	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	20
DANN	Benign	0.96
DEOGEN2	Benign	0.24	T
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.53
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.49	T
M_CAP	Pathogenic	0.52	D
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	0.0	N
PhyloP100		-0.28
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-0.29	N
REVEL	Benign	0.14
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.067	T
Vest4		0.18
MutPred		0.24		Gain of loop (P = 0.0079)
MVP		0.76
MPC		0.34
ClinPred		0.48	T
GERP RS		0.69
PromoterAI		0.26	Neutral
gMVP		0.27
Mutation Taster		=85/15	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: rs1394181436; hg19: chr3-141205939;