rs3862618

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_022370.4(ROBO3):c.1247G>A(p.Arg416His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.121 in 1,613,832 control chromosomes in the GnomAD database, including 13,613 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.096 ( 978 hom., cov: 32)

Exomes 𝑓: 0.12 ( 12635 hom. )

Consequence

ROBO3
NM_022370.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.649

Variant links:

Genes affected

ROBO3 (HGNC:13433): (roundabout guidance receptor 3) This gene is a member of the Roundabout (ROBO) gene family that controls neurite outgrowth, growth cone guidance, and axon fasciculation. ROBO proteins are a subfamily of the immunoglobulin transmembrane receptor superfamily. SLIT proteins 1-3, a family of secreted chemorepellants, are ligands for ROBO proteins and SLIT/ROBO interactions regulate myogenesis, leukocyte migration, kidney morphogenesis, angiogenesis, and vasculogenesis in addition to neurogenesis. This gene, ROBO3, has a putative extracellular domain with five immunoglobulin (Ig)-like loops and three fibronectin (Fn) type III motifs, a transmembrane segment, and a cytoplasmic tail with three conserved signaling motifs: CC0, CC2, and CC3 (CC for conserved cytoplasmic). Unlike other ROBO family members, ROBO3 lacks motif CC1. The ROBO3 gene regulates axonal navigation at the ventral midline of the neural tube. In mouse, loss of Robo3 results in a complete failure of commissural axons to cross the midline throughout the spinal cord and the hindbrain. Mutations ROBO3 result in horizontal gaze palsy with progressive scoliosis (HGPPS); an autosomal recessive disorder characterized by congenital absence of horizontal gaze, progressive scoliosis, and failure of the corticospinal and somatosensory axon tracts to cross the midline in the medulla. [provided by RefSeq, May 2019]

ROBO3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0032360852).

BP6

Variant 11-124872469-G-A is Benign according to our data. Variant chr11-124872469-G-A is described in ClinVar as [Benign]. Clinvar id is 303235.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.252 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ROBO3	NM_022370.4 linkuse as main transcript	c.1247G>A	p.Arg416His	missense_variant	8/28	ENST00000397801.6	NP_071765.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ROBO3	ENST00000397801.6 linkuse as main transcript	c.1247G>A	p.Arg416His	missense_variant	8/28	1	NM_022370.4	ENSP00000380903	P2	Q96MS0-1
ROBO3	ENST00000538940.5 linkuse as main transcript	c.1181G>A	p.Arg394His	missense_variant	7/27	5		ENSP00000441797	A2

Frequencies

GnomAD3 genomes

AF:

0.0965

AC:

14673

AN:

152066

Hom.:

979

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0250

Gnomad AMI

AF:

0.0669

Gnomad AMR

AF:

0.114

Gnomad ASJ

AF:

0.103

Gnomad EAS

AF:

0.265

Gnomad SAS

AF:

0.188

Gnomad FIN

AF:

0.0823

Gnomad MID

AF:

0.120

Gnomad NFE

AF:

0.118

Gnomad OTH

AF:

0.110

GnomAD3 exomes

AF:

0.129

AC:

32084

AN:

249226

Hom.:

2526

AF XY:

0.132

AC XY:

17839

AN XY:

135208

show subpopulations

Gnomad AFR exome

AF:

0.0211

Gnomad AMR exome

AF:

0.132

Gnomad ASJ exome

AF:

0.107

Gnomad EAS exome

AF:

0.254

Gnomad SAS exome

AF:

0.188

Gnomad FIN exome

AF:

0.0831

Gnomad NFE exome

AF:

0.117

Gnomad OTH exome

AF:

0.123

GnomAD4 exome

AF:

0.124

AC:

180855

AN:

1461648

Hom.:

12635

Cov.:

AF XY:

0.126

AC XY:

91710

AN XY:

727106

show subpopulations

Gnomad4 AFR exome

AF:

0.0193

Gnomad4 AMR exome

AF:

0.128

Gnomad4 ASJ exome

AF:

0.108

Gnomad4 EAS exome

AF:

0.291

Gnomad4 SAS exome

AF:

0.191

Gnomad4 FIN exome

AF:

0.0849

Gnomad4 NFE exome

AF:

0.117

Gnomad4 OTH exome

AF:

0.127

GnomAD4 genome

AF:

0.0964

AC:

14673

AN:

152184

Hom.:

978

Cov.:

AF XY:

0.0981

AC XY:

7298

AN XY:

74400

show subpopulations

Gnomad4 AFR

AF:

0.0250

Gnomad4 AMR

AF:

0.114

Gnomad4 ASJ

AF:

0.103

Gnomad4 EAS

AF:

0.264

Gnomad4 SAS

AF:

0.188

Gnomad4 FIN

AF:

0.0823

Gnomad4 NFE

AF:

0.119

Gnomad4 OTH

AF:

0.115

Alfa

AF:

0.120

Hom.:

2673

Bravo

AF:

0.0930

TwinsUK

AF:

0.118

AC:

437

ALSPAC

AF:

0.116

AC:

448

ESP6500AA

AF:

0.0219

AC:

ESP6500EA

AF:

0.110

AC:

932

ExAC

AF:

0.127

AC:

15329

Asia WGS

AF:

0.237

AC:

825

AN:

3478

EpiCase

AF:

0.122

EpiControl

AF:

0.124

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Gaze palsy, familial horizontal, with progressive scoliosis 1

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.63

BayesDel_noAF

Benign

-0.53

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.29

T;.

Eigen

Benign

-0.063

Eigen_PC

Benign

-0.067

FATHMM_MKL

Benign

0.65

LIST_S2

Uncertain

0.86

D;D

MetaRNN

Benign

0.0032

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.8

L;.

MutationTaster

Benign

1.0

P;P

PrimateAI

Benign

0.30

PROVEAN

Uncertain

-2.4

N;N

REVEL

Benign

0.27

Sift

Benign

0.072

T;T

Sift4G

Uncertain

0.053

T;T

Polyphen

0.73

P;.

Vest4

0.034

MPC

0.11

ClinPred

0.011

GERP RS

3.8

Varity_R

0.079

gMVP

0.24

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over