3-141487069-G-T

Variant names:

• chr3-141487069-G-T
• rs767937276
• NM_006506.5:c.-15G>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_006506.5(RASA2):​c.-15G>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00008 in 1,261,914 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00028 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000053 (0 hom.)
• Consequence: RASA2 NM_006506.5 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.773
• 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: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BS2: High AC in GnomAd4 at 42 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.-15G>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 24	NP_006497.2
	RASA2	NM_006506.5	MANE Select	c.-15G>T		5_prime_UTR	Exon 1 of 24	NP_006497.2
	RASA2	NM_001303246.3		c.-15G>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 25	NP_001290175.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RASA2	ENST00000286364.9	TSL:1 MANE Select	c.-15G>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 24	ENSP00000286364.3	Q15283-2
	RASA2	ENST00000286364.9	TSL:1 MANE Select	c.-15G>T		5_prime_UTR	Exon 1 of 24	ENSP00000286364.3	Q15283-2
	RASA2	ENST00000930693.1		c.-15G>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 25	ENSP00000600752.1

Frequencies

GnomAD3 genomes AF: 0.000280 AC: 42 AN: 150044 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000946

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000664

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000484

GnomAD2 exomes AF: 0.00 AC: 0 AN: 15774 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000531 AC: 59 AN: 1111870 Hom.: 0 Cov.: 30 AF XY: 0.0000408 AC XY: 22 AN XY: 538736

African (AFR) AF: 0.00205 AC: 44 AN: 21504

American (AMR) AF: 0.00 AC: 0 AN: 7620

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 12832

East Asian (EAS) AF: 0.00 AC: 0 AN: 22304

South Asian (SAS) AF: 0.00 AC: 0 AN: 36520

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 35798

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2812

European-Non Finnish (NFE) AF: 0.0000140 AC: 13 AN: 930114

Other (OTH) AF: 0.0000472 AC: 2 AN: 42366

GnomAD4 genome AF: 0.000280 AC: 42 AN: 150044 Hom.: 0 Cov.: 32 AF XY: 0.000191 AC XY: 14 AN XY: 73230

African (AFR) AF: 0.000946 AC: 39 AN: 41220

American (AMR) AF: 0.0000664 AC: 1 AN: 15068

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3440

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5160

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9690

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67348

Other (OTH) AF: 0.000484 AC: 1 AN: 2068

Alfa AF: 0.0000540 Hom.: 0

Bravo AF: 0.000438

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	-0.48
CADD	Benign	16
DANN	Benign	0.90
PhyloP100		0.77
PromoterAI		-0.029	Neutral

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: rs767937276; hg19: chr3-141205911;