Variant 11-124870650-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PM5

The ENST00000397801.6(ROBO3):c.955G>C(p.Glu319Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000657 in 152,182 control chromosomes in the GnomAD database, with no homozygous occurrence. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E319K) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Consequence

ROBO3
ENST00000397801.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.78

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr11-124870650-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2177.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ROBO3	NM_022370.4 linkuse as main transcript	c.955G>C	p.Glu319Gln	missense_variant	6/28	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.955G>C	p.Glu319Gln	missense_variant	6/28	1	NM_022370.4	ENSP00000380903	P2	Q96MS0-1
ROBO3	ENST00000538940.5 linkuse as main transcript	c.889G>C	p.Glu297Gln	missense_variant	5/27	5		ENSP00000441797	A2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152182

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000404

AC:

AN:

247388

Hom.:

AF XY:

0.00

AC XY:

AN XY:

134220

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:

0.00000891

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152182

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74332

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:

0.0000147

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.00000825

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Benign

-0.065

BayesDel_noAF

Benign

-0.33

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.12

T;.

Eigen

Benign

-0.062

Eigen_PC

Benign

0.070

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.87

D;D

M_CAP

Benign

0.019

MetaRNN

Uncertain

0.44

T;T

MetaSVM

Benign

-0.82

MutationAssessor

Benign

1.7

L;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Benign

0.42

PROVEAN

Benign

-0.99

N;N

REVEL

Benign

0.072

Sift

Benign

0.22

T;T

Sift4G

Benign

0.19

T;T

Polyphen

0.16

B;.

Vest4

0.36

MutPred

0.39

Loss of stability (P = 0.0703);.;

MVP

0.82

MPC

0.42

ClinPred

0.89

GERP RS

4.2

Varity_R

0.28

gMVP

0.46

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.14

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over