3-75937566-G-A

Position:

• chr3-75937566-G-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_001378191.1(ROBO2):​c.73G>A​(p.Val25Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 10/14 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Synonymous variant affecting the same amino acid position (i.e. V25V) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ROBO2 NM_001378191.1 missense
• Clinical Significance: Benign criteria provided, single submitter B:3
• Conservation: PhyloP100: 0.585

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 Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0020155013).
• BP6: Variant 3-75937566-G-A is Benign according to our data. Variant chr3-75937566-G-A is described in ClinVar as [Benign]. Clinvar id is 518349.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-75937566-G-A is described in Lovd as [Benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ROBO2	NM_001378191.1	c.73G>A	p.Val25Met	missense_variant	2/30		NP_001365120.1
ROBO2	NM_001378190.1	c.73G>A	p.Val25Met	missense_variant	2/29		NP_001365119.1
ROBO2	NM_001378195.1	c.73G>A	p.Val25Met	missense_variant	2/29		NP_001365124.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ROBO2	ENST00000696630.1	c.73G>A	p.Val25Met	missense_variant	2/30			ENSP00000512767
ROBO2	ENST00000696629.1	c.73G>A	p.Val25Met	missense_variant	2/29			ENSP00000512766
ROBO2	ENST00000471893.2	c.73G>A	p.Val25Met	missense_variant	2/29	4		ENSP00000418190

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

Alfa AF: 0.381 Hom.: 0

ExAC AF: 0.382 AC: 44297

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, single submitter

Submissions by phenotype

Vesicoureteral reflux 2 Benign:2

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	May 19, 2016	- -

ROBO2-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 18, 2020

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	7.4
DANN	Benign	0.93
Eigen	Benign	-0.93
Eigen_PC	Benign	-0.99
FATHMM_MKL	Benign	0.0019	N
LIST_S2	Benign	0.52	T;T
MetaRNN	Benign	0.0020	T;T
MetaSVM	Benign	-0.99	T
PROVEAN	Benign	0.070	N;.
REVEL	Benign	0.016
Sift	Benign	0.093	T;.
Sift4G	Uncertain	0.051	T;D
Vest4		0.082
MPC		0.22
ClinPred		0.000046	T
GERP RS		2.0
gMVP		0.17

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs78834776; hg19: chr3-75986717; COSMIC: COSV72212208;