chr11-124870795-A-G

Variant names:

• chr11-124870795-A-G
• rs7925879
• NM_022370.4:c.1033+67A>G

Variant summary

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

The NM_022370.4(ROBO3):​c.1033+67A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.69 in 1,580,152 control chromosomes in the GnomAD database, including 381,313 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 (39216 hom., cov: 31)
  • Exomes 𝑓: 0.69 (342097 hom.)
• Consequence: ROBO3 NM_022370.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.376
• 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: PanelApp Australia, ClinGen, G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.825 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022370.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ROBO3	NM_022370.4	MANE Select	c.1033+67A>G		intron	N/A	NP_071765.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ROBO3	ENST00000397801.6	TSL:1 MANE Select	c.1033+67A>G		intron	N/A	ENSP00000380903.1	Q96MS0-1
	ROBO3	ENST00000538940.5	TSL:5	c.967+67A>G		intron	N/A	ENSP00000441797.1	F5GWJ5

Frequencies

GnomAD3 genomes AF: 0.710 AC: 107862 AN: 151920 Hom.: 39183 Cov.: 31

Gnomad AFR AF: 0.832

Gnomad AMI AF: 0.706

Gnomad AMR AF: 0.552

Gnomad ASJ AF: 0.705

Gnomad EAS AF: 0.399

Gnomad SAS AF: 0.595

Gnomad FIN AF: 0.710

Gnomad MID AF: 0.726

Gnomad NFE AF: 0.704

Gnomad OTH AF: 0.706

GnomAD4 exome AF: 0.688 AC: 982688 AN: 1428112 Hom.: 342097 Cov.: 33 AF XY: 0.686 AC XY: 485095 AN XY: 706866

African (AFR) AF: 0.837 AC: 27551 AN: 32926

American (AMR) AF: 0.450 AC: 17661 AN: 39224

Ashkenazi Jewish (ASJ) AF: 0.695 AC: 17662 AN: 25406

East Asian (EAS) AF: 0.447 AC: 17106 AN: 38296

South Asian (SAS) AF: 0.598 AC: 48881 AN: 81754

European-Finnish (FIN) AF: 0.700 AC: 36143 AN: 51618

Middle Eastern (MID) AF: 0.715 AC: 4053 AN: 5670

European-Non Finnish (NFE) AF: 0.707 AC: 772947 AN: 1093912

Other (OTH) AF: 0.686 AC: 40684 AN: 59306

GnomAD4 genome AF: 0.710 AC: 107946 AN: 152040 Hom.: 39216 Cov.: 31 AF XY: 0.704 AC XY: 52300 AN XY: 74330

African (AFR) AF: 0.832 AC: 34505 AN: 41470

American (AMR) AF: 0.551 AC: 8419 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.705 AC: 2445 AN: 3468

East Asian (EAS) AF: 0.398 AC: 2054 AN: 5164

South Asian (SAS) AF: 0.594 AC: 2861 AN: 4816

European-Finnish (FIN) AF: 0.710 AC: 7490 AN: 10550

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

European-Non Finnish (NFE) AF: 0.704 AC: 47825 AN: 67966

Other (OTH) AF: 0.705 AC: 1490 AN: 2112

Alfa AF: 0.698 Hom.: 115037

Bravo AF: 0.701

Asia WGS AF: 0.551 AC: 1916 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	9.3
DANN	Benign	0.50
PhyloP100		0.38
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs7925879; hg19: chr11-124740691; COSMIC: COSV67303424;