rs1161681842

Variant names:

• chr3-141487102-G-C
• rs1161681842
• NM_006506.5:c.19G>C

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4 BS2

The NM_006506.5(RASA2):​c.19G>C​(p.Ala7Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000501 in 1,395,968 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 (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000040 (0 hom.)
• Consequence: RASA2 NM_006506.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.595
• 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.29378405).
• BS2: High AC in GnomAdExome4 at 5 AD gene.

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.19G>C	p.Ala7Pro	missense	Exon 1 of 24	NP_006497.2
	RASA2	NM_001303246.3		c.19G>C	p.Ala7Pro	missense	Exon 1 of 25	NP_001290175.1
	RASA2	NM_001303245.3		c.19G>C	p.Ala7Pro	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.19G>C	p.Ala7Pro	missense	Exon 1 of 24	ENSP00000286364.3	Q15283-2
	RASA2	ENST00000930693.1		c.19G>C	p.Ala7Pro	missense	Exon 1 of 25	ENSP00000600752.1
	RASA2	ENST00000950127.1		c.19G>C	p.Ala7Pro	missense	Exon 1 of 25	ENSP00000620186.1

Frequencies

GnomAD3 genomes AF: 0.0000133 AC: 2 AN: 150544 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.0000296

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000401 AC: 5 AN: 1245424 Hom.: 0 Cov.: 31 AF XY: 0.00000326 AC XY: 2 AN XY: 613336

African (AFR) AF: 0.00 AC: 0 AN: 25248

American (AMR) AF: 0.00 AC: 0 AN: 20580

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19270

East Asian (EAS) AF: 0.00 AC: 0 AN: 25614

South Asian (SAS) AF: 0.00 AC: 0 AN: 64232

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 43916

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3498

European-Non Finnish (NFE) AF: 0.00000503 AC: 5 AN: 994190

Other (OTH) AF: 0.00 AC: 0 AN: 48876

GnomAD4 genome AF: 0.0000133 AC: 2 AN: 150544 Hom.: 0 Cov.: 32 AF XY: 0.0000272 AC XY: 2 AN XY: 73480

African (AFR) AF: 0.00 AC: 0 AN: 41266

American (AMR) AF: 0.00 AC: 0 AN: 15130

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9944

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.0000296 AC: 2 AN: 67470

Other (OTH) AF: 0.00 AC: 0 AN: 2068

Alfa AF: 0.0000936 Hom.: 0

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	0.13
BayesDel_addAF	Benign	-0.016	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	21
DANN	Benign	0.93
DEOGEN2	Benign	0.23	T
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.35
FATHMM_MKL	Benign	0.086	N
LIST_S2	Benign	0.39	T
M_CAP	Pathogenic	0.65	D
MetaRNN	Benign	0.29	T
MetaSVM	Benign	-0.60	T
MutationAssessor	Benign	0.0	N
PhyloP100		-0.59
PrimateAI	Uncertain	0.79	T
PROVEAN	Benign	-0.22	N
REVEL	Benign	0.19
Sift	Benign	0.32	T
Sift4G	Pathogenic	0.0	D
Vest4		0.14
MutPred		0.30		Loss of helix (P = 3e-04)
MVP		0.81
MPC		0.44
ClinPred		0.29	T
GERP RS		1.5
PromoterAI		0.015	Neutral
gMVP		0.40
Mutation Taster		=93/7	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: rs1161681842; hg19: chr3-141205944;