3-141487069-G-T

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

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

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]

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RASA2	NM_006506.5	c.-15G>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 24	ENST00000286364.9	NP_006497.2
RASA2	NM_006506.5	c.-15G>T		5_prime_UTR_variant	Exon 1 of 24	ENST00000286364.9	NP_006497.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RASA2	ENST00000286364	c.-15G>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 24	1	NM_006506.5	ENSP00000286364.3
RASA2	ENST00000286364	c.-15G>T		5_prime_UTR_variant	Exon 1 of 24	1	NM_006506.5	ENSP00000286364.3

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

Gnomad4 AFR exome AF: 0.00205 AC: 44 AN: 21504

Gnomad4 AMR exome AF: 0.00 AC: 0 AN: 7620

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 12832

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 22304

Gnomad4 SAS exome AF: 0.00 AC: 0 AN: 36520

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 35798

Gnomad4 NFE exome AF: 0.0000140 AC: 13 AN: 930114

Gnomad4 Remaining exome 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

Gnomad4 AFR AF: 0.000946 AC: 0.000946143 AN: 0.000946143

Gnomad4 AMR AF: 0.0000664 AC: 0.0000663658 AN: 0.0000663658

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.000194 AC: 0.000193798 AN: 0.000193798

Gnomad4 SAS AF: 0.00 AC: 0 AN: 0

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.00 AC: 0 AN: 0

Gnomad4 OTH AF: 0.000484 AC: 0.000483559 AN: 0.000483559

Alfa AF: 0.0000540 Hom.: 0

Bravo AF: 0.000438

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 06, 2020

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: RASA2 c.-15G>T is located in the untranslated mRNA region upstream of the initiation codon. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00018 in 43946 control chromosomes (gnomAD, genomes dataset). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.-15G>T in individuals affected with Noonan Syndrome and Related Conditions and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	16
DANN	Benign	0.90

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

Publications

LitVar

Other links and lift over

dbSNP: rs767937276; hg19: chr3-141205911;