chr3-141487085-T-TGGC

Variant names:

• chr3-141487085-T-TGGC
• rs747837865
• NM_006506.5:c.13_15dupGCG

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 1P and 5B. PM4_Supporting BP6 BS2

The NM_006506.5(RASA2):​c.13_15dupGCG​(p.Ala5dup) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000435 in 1,356,370 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000042 (0 hom.)
• Consequence: RASA2 NM_006506.5 conservative_inframe_insertion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 3.08
• 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 -4 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_006506.5. Strenght limited to Supporting due to length of the change: 1aa.
• BP6: Variant 3-141487085-T-TGGC is Benign according to our data. Variant chr3-141487085-T-TGGC is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1315735.
• BS2: High AC in GnomAd4 at 8 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.13_15dupGCG	p.Ala5dup	conservative_inframe_insertion	Exon 1 of 24	NP_006497.2
	RASA2	NM_001303246.3		c.13_15dupGCG	p.Ala5dup	conservative_inframe_insertion	Exon 1 of 25	NP_001290175.1
	RASA2	NM_001303245.3		c.13_15dupGCG	p.Ala5dup	conservative_inframe_insertion	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.13_15dupGCG	p.Ala5dup	conservative_inframe_insertion	Exon 1 of 24	ENSP00000286364.3	Q15283-2
	RASA2	ENST00000930693.1		c.13_15dupGCG	p.Ala5dup	conservative_inframe_insertion	Exon 1 of 25	ENSP00000600752.1
	RASA2	ENST00000950127.1		c.13_15dupGCG	p.Ala5dup	conservative_inframe_insertion	Exon 1 of 25	ENSP00000620186.1

Frequencies

GnomAD3 genomes AF: 0.0000534 AC: 8 AN: 149682 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000663

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: 0.0000891

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000359 AC: 2 AN: 55636 AF XY: 0.0000645

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: 0.0000816

Gnomad NFE exome AF: 0.0000613

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000423 AC: 51 AN: 1206688 Hom.: 0 Cov.: 30 AF XY: 0.0000558 AC XY: 33 AN XY: 591886

African (AFR) AF: 0.00 AC: 0 AN: 23648

American (AMR) AF: 0.00 AC: 0 AN: 17936

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17164

East Asian (EAS) AF: 0.0000837 AC: 2 AN: 23888

South Asian (SAS) AF: 0.00 AC: 0 AN: 58192

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 41710

Middle Eastern (MID) AF: 0.000610 AC: 2 AN: 3278

European-Non Finnish (NFE) AF: 0.0000411 AC: 40 AN: 973898

Other (OTH) AF: 0.000149 AC: 7 AN: 46974

GnomAD4 genome AF: 0.0000534 AC: 8 AN: 149682 Hom.: 0 Cov.: 32 AF XY: 0.0000411 AC XY: 3 AN XY: 73044

African (AFR) AF: 0.00 AC: 0 AN: 40738

American (AMR) AF: 0.0000663 AC: 1 AN: 15076

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3446

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5144

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9808

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

European-Non Finnish (NFE) AF: 0.0000891 AC: 6 AN: 67358

Other (OTH) AF: 0.00 AC: 0 AN: 2064

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000567

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.1
Mutation Taster		=38/162	disease causing

Splicing

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

Other links and lift over

dbSNP: rs747837865; hg19: chr3-141205927;