3-141487078-G-A

Variant names:

• chr3-141487078-G-A
• rs773040715
• NM_006506.5:c.-6G>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_006506.5(RASA2):​c.-6G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000212 in 1,337,574 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00031 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00020 (0 hom.)
• Consequence: RASA2 NM_006506.5 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.856
• 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 -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.37).
• BS2: High AC in GnomAd4 at 47 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.-6G>A		5_prime_UTR	Exon 1 of 24	NP_006497.2
	RASA2	NM_001303246.3		c.-6G>A		5_prime_UTR	Exon 1 of 25	NP_001290175.1
	RASA2	NM_001303245.3		c.-6G>A		5_prime_UTR	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.-6G>A		5_prime_UTR	Exon 1 of 24	ENSP00000286364.3	Q15283-2
	RASA2	ENST00000930693.1		c.-6G>A		5_prime_UTR	Exon 1 of 25	ENSP00000600752.1
	RASA2	ENST00000950127.1		c.-6G>A		5_prime_UTR	Exon 1 of 25	ENSP00000620186.1

Frequencies

GnomAD3 genomes AF: 0.000314 AC: 47 AN: 149918 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000244

Gnomad AMI AF: 0.0263

Gnomad AMR AF: 0.000464

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: 0.000208

Gnomad OTH AF: 0.000484

GnomAD2 exomes AF: 0.000130 AC: 6 AN: 46160 AF XY: 0.000157

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000369

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000800

Gnomad OTH exome AF: 0.00172

GnomAD4 exome AF: 0.000200 AC: 237 AN: 1187656 Hom.: 0 Cov.: 31 AF XY: 0.000187 AC XY: 109 AN XY: 581562

African (AFR) AF: 0.000130 AC: 3 AN: 23102

American (AMR) AF: 0.000558 AC: 9 AN: 16132

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16164

East Asian (EAS) AF: 0.00 AC: 0 AN: 23384

South Asian (SAS) AF: 0.00 AC: 0 AN: 54668

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40522

Middle Eastern (MID) AF: 0.00126 AC: 4 AN: 3164

European-Non Finnish (NFE) AF: 0.000214 AC: 206 AN: 964516

Other (OTH) AF: 0.000326 AC: 15 AN: 46004

GnomAD4 genome AF: 0.000314 AC: 47 AN: 149918 Hom.: 1 Cov.: 32 AF XY: 0.000273 AC XY: 20 AN XY: 73156

African (AFR) AF: 0.0000244 AC: 1 AN: 40922

American (AMR) AF: 0.000464 AC: 7 AN: 15090

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5160

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9772

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

European-Non Finnish (NFE) AF: 0.000208 AC: 14 AN: 67412

Other (OTH) AF: 0.000484 AC: 1 AN: 2066

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.000450

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.37
CADD	Benign	17
DANN	Benign	0.94
PhyloP100		0.86
PromoterAI		-0.13	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=298/2	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: rs773040715; hg19: chr3-141205920;