rs542280581

Variant names:

• chr3-77040327-G-A
• rs542280581
• NM_001395656.1:c.-459G>A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001395656.1(ROBO2):​c.-459G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00504 in 995,630 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0037 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0053 (13 hom.)
• Consequence: ROBO2 NM_001395656.1 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.20

Genes affected

ROBO2 (HGNC:10250): (roundabout guidance receptor 2) The protein encoded by this gene belongs to the ROBO family, part of the immunoglobulin superfamily of proteins that are highly conserved from fly to human. The encoded protein is a transmembrane receptor for the slit homolog 2 protein and functions in axon guidance and cell migration. Mutations in this gene are associated with vesicoureteral reflux, characterized by the backward flow of urine from the bladder into the ureters or the kidney. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2014]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 3-77040327-G-A is Benign according to our data. Variant chr3-77040327-G-A is described in ClinVar as [Benign]. Clinvar id is 346669.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 563 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ROBO2	NM_001395656.1	c.-459G>A		5_prime_UTR_variant	Exon 1 of 28	ENST00000696593.1	NP_001382585.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ROBO2	ENST00000696593	c.-459G>A		5_prime_UTR_variant	Exon 1 of 28		NM_001395656.1	ENSP00000512738.1

Frequencies

GnomAD3 genomes AF: 0.00371 AC: 564 AN: 152168 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.000989

Gnomad AMI AF: 0.0417

Gnomad AMR AF: 0.00268

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.00330

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00584

Gnomad OTH AF: 0.00191

GnomAD4 exome AF: 0.00529 AC: 4458 AN: 843344 Hom.: 13 Cov.: 33 AF XY: 0.00517 AC XY: 2016 AN XY: 390136

Gnomad4 AFR exome AF: 0.000314

Gnomad4 AMR exome AF: 0.000561

Gnomad4 ASJ exome AF: 0.000188

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000406

Gnomad4 FIN exome AF: 0.00348

Gnomad4 NFE exome AF: 0.00556

Gnomad4 OTH exome AF: 0.00572

GnomAD4 genome AF: 0.00370 AC: 563 AN: 152286 Hom.: 3 Cov.: 32 AF XY: 0.00353 AC XY: 263 AN XY: 74466

Gnomad4 AFR AF: 0.000986

Gnomad4 AMR AF: 0.00268

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.00330

Gnomad4 NFE AF: 0.00584

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00476 Hom.: 1

Bravo AF: 0.00361

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Vesicoureteral reflux 2 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	10
DANN	Benign	0.83

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs542280581; hg19: chr3-77089478;