3-77040382-G-C

Position:

• chr3-77040382-G-C

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_001395656.1(ROBO2):​c.-404G>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 0.00745 in 1,008,888 control chromosomes in the GnomAD database, including 415 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.033 (278 hom., cov: 32)
  • Exomes 𝑓: 0.0029 (137 hom.)
• Consequence: ROBO2 NM_001395656.1 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 3.21

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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.34).
• BP6: Variant 3-77040382-G-C is Benign according to our data. Variant chr3-77040382-G-C is described in ClinVar as [Benign]. Clinvar id is 346670.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.11 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ROBO2	NM_001395656.1	c.-404G>C		5_prime_UTR_variant	1/28	ENST00000696593.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ROBO2	ENST00000696593.1	c.-404G>C		5_prime_UTR_variant	1/28		NM_001395656.1	A2

Frequencies

GnomAD3 genomes AF: 0.0327 AC: 4975 AN: 152164 Hom.: 278 Cov.: 32

Gnomad AFR AF: 0.113

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0100

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00482

Gnomad SAS AF: 0.0147

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.0191

GnomAD4 exome AF: 0.00294 AC: 2517 AN: 856606 Hom.: 137 Cov.: 33 AF XY: 0.00281 AC XY: 1116 AN XY: 396744

Gnomad4 AFR exome AF: 0.123

Gnomad4 AMR exome AF: 0.00568

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00219

Gnomad4 SAS exome AF: 0.0124

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000746

Gnomad4 OTH exome AF: 0.00678

GnomAD4 genome AF: 0.0328 AC: 4995 AN: 152282 Hom.: 278 Cov.: 32 AF XY: 0.0326 AC XY: 2427 AN XY: 74470

Gnomad4 AFR AF: 0.113

Gnomad4 AMR AF: 0.0100

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00503

Gnomad4 SAS AF: 0.0149

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000250

Gnomad4 OTH AF: 0.0184

Alfa AF: 0.000580 Hom.: 0

Bravo AF: 0.0364

Asia WGS AF: 0.0150 AC: 53 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	Jun 20, 2021	- -

Vesicoureteral reflux 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.34
CADD	Benign	20
DANN	Benign	0.91

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs79942150; hg19: chr3-77089533;