11-124870514-A-T

Variant names:

• chr11-124870514-A-T
• rs3923890
• NM_022370.4:c.906-87A>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_022370.4(ROBO3):​c.906-87A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.689 in 1,586,522 control chromosomes in the GnomAD database, including 381,148 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.71 (39086 hom., cov: 32)
  • Exomes 𝑓: 0.69 (342062 hom.)
• Consequence: ROBO3 NM_022370.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.262
• Publications: 9 publications found

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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.825 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ROBO3	NM_022370.4	c.906-87A>T		intron_variant	Intron 5 of 27	ENST00000397801.6	NP_071765.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ROBO3	ENST00000397801.6	c.906-87A>T		intron_variant	Intron 5 of 27	1	NM_022370.4	ENSP00000380903.1
ROBO3	ENST00000538940.5	c.840-87A>T		intron_variant	Intron 4 of 26	5		ENSP00000441797.1

Frequencies

GnomAD3 genomes AF: 0.709 AC: 107692 AN: 151982 Hom.: 39054 Cov.: 32

Gnomad AFR AF: 0.832

Gnomad AMI AF: 0.705

Gnomad AMR AF: 0.552

Gnomad ASJ AF: 0.657

Gnomad EAS AF: 0.399

Gnomad SAS AF: 0.594

Gnomad FIN AF: 0.709

Gnomad MID AF: 0.728

Gnomad NFE AF: 0.703

Gnomad OTH AF: 0.704

GnomAD4 exome AF: 0.686 AC: 984711 AN: 1434422 Hom.: 342062 Cov.: 29 AF XY: 0.685 AC XY: 487080 AN XY: 711456

African (AFR) AF: 0.836 AC: 27670 AN: 33080

American (AMR) AF: 0.448 AC: 18263 AN: 40734

Ashkenazi Jewish (ASJ) AF: 0.652 AC: 16665 AN: 25566

East Asian (EAS) AF: 0.446 AC: 17346 AN: 38876

South Asian (SAS) AF: 0.597 AC: 48882 AN: 81880

European-Finnish (FIN) AF: 0.700 AC: 36406 AN: 52014

Middle Eastern (MID) AF: 0.714 AC: 4085 AN: 5720

European-Non Finnish (NFE) AF: 0.706 AC: 774746 AN: 1097050

Other (OTH) AF: 0.683 AC: 40648 AN: 59502

GnomAD4 genome AF: 0.709 AC: 107774 AN: 152100 Hom.: 39086 Cov.: 32 AF XY: 0.702 AC XY: 52206 AN XY: 74344

African (AFR) AF: 0.832 AC: 34536 AN: 41510

American (AMR) AF: 0.551 AC: 8420 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.657 AC: 2279 AN: 3470

East Asian (EAS) AF: 0.398 AC: 2049 AN: 5154

South Asian (SAS) AF: 0.593 AC: 2853 AN: 4812

European-Finnish (FIN) AF: 0.709 AC: 7507 AN: 10584

Middle Eastern (MID) AF: 0.724 AC: 213 AN: 294

European-Non Finnish (NFE) AF: 0.703 AC: 47792 AN: 67972

Other (OTH) AF: 0.704 AC: 1483 AN: 2106

Alfa AF: 0.706 Hom.: 4795

Bravo AF: 0.700

Asia WGS AF: 0.552 AC: 1919 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	7.5
DANN	Benign	0.82
PhyloP100		-0.26
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs3923890; hg19: chr11-124740410;