NM_001395656.1:c.-459G>A

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 0 publications found

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]

ROBO2 Gene-Disease associations (from GenCC):

• vesicoureteral reflux 2

  Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• familial vesicoureteral reflux

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 346669.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 563 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001395656.1. 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
	ROBO2	NM_001395656.1	MANE Select	c.-459G>A		5_prime_UTR	Exon 1 of 28	NP_001382585.1	A0A8Q3WLE3
	ROBO2	NM_001378193.1		c.-459G>A		5_prime_UTR	Exon 1 of 27	NP_001365122.1	H7C4J7
	ROBO2	NM_001290040.2		c.-459G>A		5_prime_UTR	Exon 1 of 28	NP_001276969.1	F8W703

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ROBO2	ENST00000696593.1	MANE Select	c.-459G>A		5_prime_UTR	Exon 1 of 28	ENSP00000512738.1	A0A8Q3WLE3
	ROBO2	ENST00000461745.5	TSL:1	c.-459G>A		5_prime_UTR	Exon 1 of 26	ENSP00000417164.1	Q9HCK4-1
	ROBO2	ENST00000705983.1		c.-459G>A		5_prime_UTR	Exon 1 of 27	ENSP00000516193.1	A0A994J7I9

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

African (AFR) AF: 0.000314 AC: 5 AN: 15924

American (AMR) AF: 0.000561 AC: 1 AN: 1782

Ashkenazi Jewish (ASJ) AF: 0.000188 AC: 1 AN: 5310

East Asian (EAS) AF: 0.00 AC: 0 AN: 3982

South Asian (SAS) AF: 0.000406 AC: 7 AN: 17230

European-Finnish (FIN) AF: 0.00348 AC: 2 AN: 574

Middle Eastern (MID) AF: 0.00183 AC: 3 AN: 1642

European-Non Finnish (NFE) AF: 0.00556 AC: 4280 AN: 769104

Other (OTH) AF: 0.00572 AC: 159 AN: 27796

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

African (AFR) AF: 0.000986 AC: 41 AN: 41574

American (AMR) AF: 0.00268 AC: 41 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4818

European-Finnish (FIN) AF: 0.00330 AC: 35 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00584 AC: 397 AN: 68008

Other (OTH) AF: 0.00189 AC: 4 AN: 2114

Alfa AF: 0.00476 Hom.: 1

Bravo AF: 0.00361

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	10
DANN	Benign	0.83
PhyloP100		2.2
PromoterAI		0.048	Neutral

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

Other links and lift over

dbSNP: rs542280581; hg19: chr3-77089478; COSMIC: COSV107401650;