chr3-141487097-C-A

Variant names:

• chr3-141487097-C-A
• rs1394181436
• NM_006506.5:c.14C>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>A​(p.Ala5Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000163 in 1,230,644 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. 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. A5V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000016 (0 hom.)
• Consequence: RASA2 NM_006506.5 missense
• Clinical Significance: Not reported in ClinVar
• 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=0.18187171).

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>A	p.Ala5Glu	missense	Exon 1 of 24	NP_006497.2
	RASA2	NM_001303246.3		c.14C>A	p.Ala5Glu	missense	Exon 1 of 25	NP_001290175.1
	RASA2	NM_001303245.3		c.14C>A	p.Ala5Glu	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>A	p.Ala5Glu	missense	Exon 1 of 24	ENSP00000286364.3	Q15283-2
	RASA2	ENST00000930693.1		c.14C>A	p.Ala5Glu	missense	Exon 1 of 25	ENSP00000600752.1
	RASA2	ENST00000950127.1		c.14C>A	p.Ala5Glu	missense	Exon 1 of 25	ENSP00000620186.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000163 AC: 2 AN: 1230644 Hom.: 0 Cov.: 31 AF XY: 0.00000165 AC XY: 1 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: 0.0000401 AC: 1 AN: 24932

South Asian (SAS) AF: 0.00 AC: 0 AN: 62004

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: 986974

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

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	0.0027	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	19
DANN	Benign	0.94
DEOGEN2	Benign	0.23	T
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.47	T
M_CAP	Pathogenic	0.61	D
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	0.0	N
PhyloP100		-0.28
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-0.13	N
REVEL	Benign	0.14
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.041	D
Vest4		0.22
MutPred		0.21		Gain of solvent accessibility (P = 0.0411)
MVP		0.74
MPC		0.40
ClinPred		0.61	D
GERP RS		0.69
PromoterAI		0.069	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.0
gMVP		0.40
Mutation Taster		=83/17	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;