chr3-75937590-G-T

Variant names:

• chr3-75937590-G-T
• rs747011633
• NM_001378191.1:c.97G>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP6

The NM_001378191.1(ROBO2):​c.97G>T​(p.Gly33*) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ROBO2 NM_001378191.1 stop_gained
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 5.00
• Publications: 1 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, Labcorp Genetics (formerly Invitae)
• familial vesicoureteral reflux

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 3-75937590-G-T is Benign according to our data. Variant chr3-75937590-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 224347.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001378191.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ROBO2	NM_001378191.1		c.97G>T	p.Gly33*	stop_gained	Exon 2 of 30	NP_001365120.1
	ROBO2	NM_001378190.1		c.97G>T	p.Gly33*	stop_gained	Exon 2 of 29	NP_001365119.1
	ROBO2	NM_001378195.1		c.97G>T	p.Gly33*	stop_gained	Exon 2 of 29	NP_001365124.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ROBO2	ENST00000696630.1		c.97G>T	p.Gly33*	stop_gained	Exon 2 of 30	ENSP00000512767.1
	ROBO2	ENST00000696629.1		c.97G>T	p.Gly33*	stop_gained	Exon 2 of 29	ENSP00000512766.1
	ROBO2	ENST00000471893.2	TSL:4	c.97G>T	p.Gly33*	stop_gained	Exon 2 of 29	ENSP00000418190.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.0195 AC: 3534 AN: 181206 AF XY: 0.0197

Gnomad AFR exome AF: 0.00163

Gnomad AMR exome AF: 0.0215

Gnomad ASJ exome AF: 0.0327

Gnomad EAS exome AF: 0.0000573

Gnomad FIN exome AF: 0.0168

Gnomad NFE exome AF: 0.0275

Gnomad OTH exome AF: 0.0226

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1403380 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 695790

African (AFR) AF: 0.00 AC: 0 AN: 32768

American (AMR) AF: 0.00 AC: 0 AN: 40318

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25100

East Asian (EAS) AF: 0.00 AC: 0 AN: 38562

South Asian (SAS) AF: 0.00 AC: 0 AN: 79448

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 36126

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5684

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1086834

Other (OTH) AF: 0.00 AC: 0 AN: 58540

GnomAD4 genome Cov.: 31

Alfa AF: 0.124 Hom.: 0

ExAC AF: 0.0736 AC: 8607

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	40
DANN	Uncertain	0.99
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Uncertain	0.82	D
PhyloP100		5.0
Vest4		0.50
GERP RS		4.5

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs747011633; hg19: chr3-75986741; COSMIC: COSV72213580;