11-124870035-C-T

Variant names:

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP3_StrongPP5

The NM_022370.4(ROBO3):c.733C>T(p.Arg245Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000235 in 1,613,822 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000025 ( 0 hom. )

Consequence

ROBO3
NM_022370.4 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 1.14

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 Likely_pathogenic. Variant got 7 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.959

PP5

Variant 11-124870035-C-T is Pathogenic according to our data. Variant chr11-124870035-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2184.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ROBO3	NM_022370.4 link	c.733C>T	p.Arg245Trp	missense_variant	Exon 4 of 28	ENST00000397801.6	NP_071765.2	Q96MS0-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ROBO3	ENST00000397801.6 link	c.733C>T	p.Arg245Trp	missense_variant	Exon 4 of 28	1	NM_022370.4	ENSP00000380903.1		Q96MS0-1
ROBO3	ENST00000538940.5 link	c.667C>T	p.Arg223Trp	missense_variant	Exon 3 of 27	5		ENSP00000441797.1		F5GWJ5

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152152

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000120

AC:

AN:

249078

Hom.:

AF XY:

0.00000740

AC XY:

AN XY:

135186

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000266

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000253

AC:

AN:

1461670

Hom.:

Cov.:

AF XY:

0.0000193

AC XY:

AN XY:

727116

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000279

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152152

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74310

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.0000844

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.00000827

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Gaze palsy, familial horizontal, with progressive scoliosis 1

Pathogenic:3

Jan 09, 2021

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

This ROBO3 variant was reported as Pathogenicâ€‹ in PMID: 16525029; PMID: 19633821 with original nomenclature reported as 733C->T, R245W, c.733C>T, R245W. Variant was re-classified as Likely Pathogenic based on the criteria PM2_Supporting, PM3_Strong, PP3_Supporting, PP4_Supporting. -

Mar 01, 2006

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Neuberg Centre For Genomic Medicine, NCGM

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The observed missense c.733C>T(p.Arg245Trp) variant in ROBO3 gene has been reported in homozygous or compound heterozygous state in multiple individuals affected with Horizontal Gaze Palsy (Chan WM, et. al.,2006; Amouri R, et. al., 2009). This variant has been observed to segregate with disease (Chan WM, et. al.,2006). This variant is present with an allele frequency of 0.001% in gnomAD Exomes database. This variant has been submitted to the ClinVar database as Uncertain Significance/ Pathogenic/ Likely Pathogenic. The amino acid change p.Arg245Trp in ROBO3 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Arg at position 245 is changed to a Trp changing protein sequence and it might alter its composition and physico-chemical properties. Functional studies are required to prove pathogenicity of the variant. For these reasons, this variant has been classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.50

BayesDel_addAF

Uncertain

0.16

BayesDel_noAF

Uncertain

-0.010

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.54

D;.

Eigen

Uncertain

0.33

Eigen_PC

Uncertain

0.26

FATHMM_MKL

Uncertain

0.89

LIST_S2

Pathogenic

1.0

D;D

M_CAP

Uncertain

0.14

MetaRNN

Pathogenic

0.96

D;D

MetaSVM

Uncertain

0.18

MutationAssessor

Benign

2.0

M;.

PrimateAI

Uncertain

0.50

PROVEAN

Pathogenic

-7.3

D;D

REVEL

Pathogenic

0.72

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;.

Vest4

0.69

MutPred

0.85

Loss of disorder (P = 0.0172);.;

MVP

0.81

MPC

0.48

ClinPred

0.90

GERP RS

3.8

Varity_R

0.85

gMVP

0.78

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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