5-87267937-C-T

Variant names:

• chr5-87267937-C-T
• rs147012315
• NM_002890.3:c.-515C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_002890.3(RASA1):​c.-515C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.014 in 367,460 control chromosomes in the GnomAD database, including 62 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.012 (11 hom., cov: 31)
  • Exomes 𝑓: 0.015 (51 hom.)
• Consequence: RASA1 NM_002890.3 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.15
• Publications: 0 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 5-87267937-C-T is Benign according to our data. Variant chr5-87267937-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1219209.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0124 (1840/148750) while in subpopulation NFE AF = 0.0181 (1211/66968). AF 95% confidence interval is 0.0172. There are 11 homozygotes in GnomAd4. There are 895 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1840 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002890.3. 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.-515C>T		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.-515C>T		5_prime_UTR	Exon 1 of 25	ENSP00000274376.6	P20936-1
	RASA1	ENST00000515800.6	TSL:1	n.-515C>T		non_coding_transcript_exon	Exon 1 of 26	ENSP00000423395.2	P20936-3
	RASA1	ENST00000515800.6	TSL:1	n.-515C>T		5_prime_UTR	Exon 1 of 26	ENSP00000423395.2	P20936-3

Frequencies

GnomAD3 genomes AF: 0.0124 AC: 1839 AN: 148634 Hom.: 11 Cov.: 31

Gnomad AFR AF: 0.00265

Gnomad AMI AF: 0.0310

Gnomad AMR AF: 0.0114

Gnomad ASJ AF: 0.000877

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00366

Gnomad FIN AF: 0.0272

Gnomad MID AF: 0.00667

Gnomad NFE AF: 0.0181

Gnomad OTH AF: 0.00938

GnomAD4 exome AF: 0.0151 AC: 3313 AN: 218710 Hom.: 51 Cov.: 0 AF XY: 0.0151 AC XY: 1693 AN XY: 111768

African (AFR) AF: 0.00435 AC: 28 AN: 6432

American (AMR) AF: 0.0106 AC: 74 AN: 6992

Ashkenazi Jewish (ASJ) AF: 0.00122 AC: 10 AN: 8194

East Asian (EAS) AF: 0.00 AC: 0 AN: 19568

South Asian (SAS) AF: 0.00205 AC: 5 AN: 2442

European-Finnish (FIN) AF: 0.0310 AC: 507 AN: 16344

Middle Eastern (MID) AF: 0.00345 AC: 4 AN: 1158

European-Non Finnish (NFE) AF: 0.0174 AC: 2492 AN: 143082

Other (OTH) AF: 0.0133 AC: 193 AN: 14498

GnomAD4 genome AF: 0.0124 AC: 1840 AN: 148750 Hom.: 11 Cov.: 31 AF XY: 0.0123 AC XY: 895 AN XY: 72564

African (AFR) AF: 0.00265 AC: 108 AN: 40818

American (AMR) AF: 0.0113 AC: 170 AN: 14996

Ashkenazi Jewish (ASJ) AF: 0.000877 AC: 3 AN: 3422

East Asian (EAS) AF: 0.00 AC: 0 AN: 4560

South Asian (SAS) AF: 0.00389 AC: 17 AN: 4372

European-Finnish (FIN) AF: 0.0272 AC: 282 AN: 10384

Middle Eastern (MID) AF: 0.00719 AC: 2 AN: 278

European-Non Finnish (NFE) AF: 0.0181 AC: 1211 AN: 66968

Other (OTH) AF: 0.00928 AC: 19 AN: 2048

Alfa AF: 0.0139 Hom.: 2

Bravo AF: 0.0110

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely 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
BayesDel_noAF	Benign	-0.51
CADD	Benign	17
DANN	Benign	0.79
PhyloP100		3.2
PromoterAI		0.29	Neutral
Mutation Taster		=288/12	polymorphism

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: rs147012315; hg19: chr5-86563754;