3-77040244-T-C

Position:

• chr3-77040244-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001395656.1(ROBO2):​c.-542T>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.369 in 987,786 control chromosomes in the GnomAD database, including 70,708 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.45 (17069 hom., cov: 32)
  • Exomes 𝑓: 0.35 (53639 hom.)
• Consequence: ROBO2 NM_001395656.1 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.386

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 3-77040244-T-C is Benign according to our data. Variant chr3-77040244-T-C is described in ClinVar as [Benign]. Clinvar id is 346667.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.67 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ROBO2	NM_001395656.1	c.-542T>C		5_prime_UTR_variant	1/28	ENST00000696593.1	NP_001382585.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ROBO2	ENST00000696593.1	c.-542T>C		5_prime_UTR_variant	1/28		NM_001395656.1	ENSP00000512738	A2

Frequencies

GnomAD3 genomes AF: 0.450 AC: 68376 AN: 151880 Hom.: 17027 Cov.: 32

Gnomad AFR AF: 0.676

Gnomad AMI AF: 0.595

Gnomad AMR AF: 0.438

Gnomad ASJ AF: 0.339

Gnomad EAS AF: 0.393

Gnomad SAS AF: 0.388

Gnomad FIN AF: 0.327

Gnomad MID AF: 0.418

Gnomad NFE AF: 0.348

Gnomad OTH AF: 0.425

GnomAD4 exome AF: 0.354 AC: 295907 AN: 835788 Hom.: 53639 Cov.: 34 AF XY: 0.352 AC XY: 136128 AN XY: 386238

Gnomad4 AFR exome AF: 0.704

Gnomad4 AMR exome AF: 0.432

Gnomad4 ASJ exome AF: 0.338

Gnomad4 EAS exome AF: 0.403

Gnomad4 SAS exome AF: 0.372

Gnomad4 FIN exome AF: 0.301

Gnomad4 NFE exome AF: 0.346

Gnomad4 OTH exome AF: 0.368

GnomAD4 genome AF: 0.451 AC: 68494 AN: 151998 Hom.: 17069 Cov.: 32 AF XY: 0.451 AC XY: 33515 AN XY: 74298

Gnomad4 AFR AF: 0.677

Gnomad4 AMR AF: 0.438

Gnomad4 ASJ AF: 0.339

Gnomad4 EAS AF: 0.394

Gnomad4 SAS AF: 0.389

Gnomad4 FIN AF: 0.327

Gnomad4 NFE AF: 0.348

Gnomad4 OTH AF: 0.426

Alfa AF: 0.367 Hom.: 15389

Bravo AF: 0.465

Asia WGS AF: 0.430 AC: 1495 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	- -

Vesicoureteral reflux 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	16
DANN	Benign	0.63

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs3923745; hg19: chr3-77089395;