ENST00000274376:c.-493dupA

Variant names:

• chr5-87267958-C-CA
• rs3840522
• NM_002890.3:c.-493dupA

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The ENST00000274376.11(RASA1):​c.-493dupA variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.193 in 398,582 control chromosomes in the GnomAD database, including 8,226 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.18 (2733 hom., cov: 24)
  • Exomes 𝑓: 0.20 (5493 hom.)
• Consequence: RASA1 ENST00000274376.11 5_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.867
• Publications: 1 publications found

Genes affected

RASA1 (HGNC:9871): (RAS p21 protein activator 1) The protein encoded by this gene is located in the cytoplasm and is part 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. Mutations leading to changes in the binding sites of either protein are associated with basal cell carcinomas. Mutations also have been associated with hereditary capillary malformations (CM) with or without arteriovenous malformations (AVM) and Parkes Weber syndrome. Alternative splicing results in two isoforms where the shorter isoform, lacking the N-terminal hydrophobic region but retaining the same activity, appears to be abundantly expressed in placental but not adult tissues. [provided by RefSeq, May 2012]

RASA1 Gene-Disease associations (from GenCC):

• capillary malformation-arteriovenous malformation 1

  Inheritance: AD Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics, G2P
• capillary malformation-arteriovenous malformation syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Parkes Weber syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• cardiofaciocutaneous syndrome

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• Costello syndrome

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• Noonan 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
• telangiectasia, hereditary hemorrhagic, type 1

  Inheritance: AD Classification: NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae)

ENSG00000303897 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP6: Variant 5-87267958-C-CA is Benign according to our data. Variant chr5-87267958-C-CA is described in ClinVar as Benign. ClinVar VariationId is 1252411.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.415 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000274376.11. 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
	RASA1	NM_002890.3	MANE Select	c.-493dupA		5_prime_UTR	Exon 1 of 25	NP_002881.1	P20936-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RASA1	ENST00000274376.11	TSL:1 MANE Select	c.-493dupA		5_prime_UTR	Exon 1 of 25	ENSP00000274376.6	P20936-1
	RASA1	ENST00000515800.6	TSL:1	n.-493dupA		non_coding_transcript_exon	Exon 1 of 26	ENSP00000423395.2	P20936-3
	RASA1	ENST00000515800.6	TSL:1	n.-493dupA		5_prime_UTR	Exon 1 of 26	ENSP00000423395.2	P20936-3

Frequencies

GnomAD3 genomes AF: 0.181 AC: 27331 AN: 151128 Hom.: 2740 Cov.: 24

Gnomad AFR AF: 0.145

Gnomad AMI AF: 0.226

Gnomad AMR AF: 0.140

Gnomad ASJ AF: 0.215

Gnomad EAS AF: 0.431

Gnomad SAS AF: 0.322

Gnomad FIN AF: 0.114

Gnomad MID AF: 0.259

Gnomad NFE AF: 0.191

Gnomad OTH AF: 0.185

GnomAD4 exome AF: 0.200 AC: 49443 AN: 247338 Hom.: 5493 Cov.: 0 AF XY: 0.201 AC XY: 25304 AN XY: 125590

African (AFR) AF: 0.144 AC: 1036 AN: 7170

American (AMR) AF: 0.134 AC: 1031 AN: 7688

Ashkenazi Jewish (ASJ) AF: 0.209 AC: 1921 AN: 9202

East Asian (EAS) AF: 0.345 AC: 7838 AN: 22710

South Asian (SAS) AF: 0.334 AC: 1034 AN: 3098

European-Finnish (FIN) AF: 0.128 AC: 2650 AN: 20664

Middle Eastern (MID) AF: 0.264 AC: 340 AN: 1288

European-Non Finnish (NFE) AF: 0.190 AC: 30165 AN: 159128

Other (OTH) AF: 0.209 AC: 3428 AN: 16390

GnomAD4 genome AF: 0.181 AC: 27322 AN: 151244 Hom.: 2733 Cov.: 24 AF XY: 0.180 AC XY: 13340 AN XY: 73906

African (AFR) AF: 0.145 AC: 5970 AN: 41284

American (AMR) AF: 0.139 AC: 2127 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.215 AC: 742 AN: 3458

East Asian (EAS) AF: 0.430 AC: 2172 AN: 5050

South Asian (SAS) AF: 0.322 AC: 1533 AN: 4754

European-Finnish (FIN) AF: 0.114 AC: 1193 AN: 10466

Middle Eastern (MID) AF: 0.245 AC: 72 AN: 294

European-Non Finnish (NFE) AF: 0.191 AC: 12919 AN: 67670

Other (OTH) AF: 0.185 AC: 388 AN: 2100

Alfa AF: 0.0501 Hom.: 46

Asia WGS AF: 0.316 AC: 1102 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.87
Mutation Taster		=300/0	polymorphism (auto)

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: rs3840522; hg19: chr5-86563775; COSMIC: COSV57198437;