Genetic Variant ROBO3:p.Gly456Arg (chr11-124872919-G-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_022370.4(ROBO3):c.1366G>C(p.Gly456Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,012 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

ROBO3
NM_022370.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 8.06

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

gaze palsy, familial horizontal, with progressive scoliosis 1
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, ClinGen, Genomics England PanelApp

ROBO3 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ROBO3	NM_022370.4 link	c.1366G>C	p.Gly456Arg	missense_variant	Exon 9 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.1366G>C	p.Gly456Arg	missense_variant	Exon 9 of 28	1	NM_022370.4	ENSP00000380903.1		Q96MS0-1
ROBO3	ENST00000538940.5 link	c.1300G>C	p.Gly434Arg	missense_variant	Exon 8 of 27	5		ENSP00000441797.1		F5GWJ5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1459012

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

725800

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33424

American (AMR)

AF:

0.00

AC:

AN:

44644

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26006

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.00

AC:

AN:

86034

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53346

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4532

European-Non Finnish (NFE)

AF:

9.00e-7

AC:

AN:

1111134

Other (OTH)

AF:

0.00

AC:

AN:

60196

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.93

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Uncertain

-0.080

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.48

T;.

Eigen

Uncertain

0.66

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.97

D;D

M_CAP

Benign

0.020

MetaRNN

Uncertain

0.72

D;D

MetaSVM

Benign

-0.88

MutationAssessor

Benign

0.45

N;.

PhyloP100

8.1

PrimateAI

Uncertain

0.64

PROVEAN

Pathogenic

-7.7

D;D

REVEL

Uncertain

0.50

Sift

Pathogenic

0.0

D;D

Sift4G

Uncertain

0.0020

D;D

Polyphen

1.0

D;.

Vest4

0.70

MutPred

0.52

Gain of solvent accessibility (P = 0.0789);.;

MVP

0.65

MPC

0.51

ClinPred

1.0

GERP RS

4.6

Varity_R

0.91

gMVP

0.89

Mutation Taster

=31/69

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over