5-87267937-C-T

Variant summary

Our verdict is Benign. Variant got -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

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]

ACMG classification

Verdict is Benign. Variant got -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 id 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 male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd at 1839 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RASA1	NM_002890.3	c.-515C>T		5_prime_UTR_variant	1/25	ENST00000274376.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RASA1	ENST00000274376.11	c.-515C>T		5_prime_UTR_variant	1/25	1	NM_002890.3	P2
RASA1	ENST00000515800.6	c.-515C>T		5_prime_UTR_variant, NMD_transcript_variant	1/26	1

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

Gnomad4 AFR exome AF: 0.00435

Gnomad4 AMR exome AF: 0.0106

Gnomad4 ASJ exome AF: 0.00122

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00205

Gnomad4 FIN exome AF: 0.0310

Gnomad4 NFE exome AF: 0.0174

Gnomad4 OTH exome AF: 0.0133

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

Gnomad4 AFR AF: 0.00265

Gnomad4 AMR AF: 0.0113

Gnomad4 ASJ AF: 0.000877

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00389

Gnomad4 FIN AF: 0.0272

Gnomad4 NFE AF: 0.0181

Gnomad4 OTH AF: 0.00928

Alfa AF: 0.0139 Hom.: 2

Bravo AF: 0.0110

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 26, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
Cadd	Benign	17
Dann	Benign	0.79

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: rs147012315; hg19: chr5-86563754;