3-141487089-G-GGCGGCGGCGCCTGCTGCT

Position:

• chr3-141487089-G-GGCGGCGGCGCCTGCTGCT

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PM4

The NM_006506.5(RASA2):​c.15_32dup​(p.Pro6_Ala11dup) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000497 in 1,367,670 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00017 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000035 (0 hom.)
• Consequence: RASA2 NM_006506.5 inframe_insertion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.08

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

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a modified_residue N-acetylalanine (size 0) in uniprot entity RASA2_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_006506.5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RASA2	NM_006506.5	c.15_32dup	p.Pro6_Ala11dup	inframe_insertion	1/24	ENST00000286364.9
RASA2	NM_001303245.3	c.15_32dup	p.Pro6_Ala11dup	inframe_insertion	1/24
RASA2	NM_001303246.3	c.15_32dup	p.Pro6_Ala11dup	inframe_insertion	1/25
RASA2	XM_047448652.1	c.15_32dup	p.Pro6_Ala11dup	inframe_insertion	1/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RASA2	ENST00000286364.9	c.15_32dup	p.Pro6_Ala11dup	inframe_insertion	1/24	1	NM_006506.5	P1
RASA2	ENST00000515549.1	c.15_32dup	p.Pro6_Ala11dup	inframe_insertion, NMD_transcript_variant	1/5	4

Frequencies

GnomAD3 genomes AF: 0.000166 AC: 25 AN: 150440 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000485

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000405

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000168 AC: 1 AN: 59442 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 33384

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000800

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000353 AC: 43 AN: 1217120 Hom.: 0 Cov.: 30 AF XY: 0.0000301 AC XY: 18 AN XY: 597624

Gnomad4 AFR exome AF: 0.000871

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000413

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000260

Gnomad4 NFE exome AF: 0.00000817

Gnomad4 OTH exome AF: 0.0000421

GnomAD4 genome AF: 0.000166 AC: 25 AN: 150550 Hom.: 0 Cov.: 32 AF XY: 0.000163 AC XY: 12 AN XY: 73550

Gnomad4 AFR AF: 0.000483

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.000405

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 10, 2023

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. ClinVar contains an entry for this variant (Variation ID: 2421860). This variant has not been reported in the literature in individuals affected with RASA2-related conditions. This variant is present in population databases (rs772613760, gnomAD 0.06%). This variant, c.15_32dup, results in the insertion of 6 amino acid(s) of the RASA2 protein (p.Pro6_Ala11dup), but otherwise preserves the integrity of the reading frame. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs769524904; hg19: chr3-141205931;