11-124879688-C-G

Variant names:

• chr11-124879688-C-G
• rs3802905
• NM_022370.4:c.3797-99C>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.3797-99C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.362 in 1,556,208 control chromosomes in the GnomAD database, including 108,676 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 0.40 (13242 hom., cov: 31)
  • Exomes 𝑓: 0.36 (95434 hom.)
• Consequence: ROBO3 NM_022370.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0510
• Publications: 4 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=-0.74).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.545 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.3797-99C>G		intron	N/A	NP_071765.2
	ROBO3	NM_001370356.1		c.944-99C>G		intron	N/A	NP_001357285.1
	ROBO3	NM_001370357.1		c.944-99C>G		intron	N/A	NP_001357286.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ROBO3	ENST00000397801.6	TSL:1 MANE Select	c.3797-99C>G		intron	N/A	ENSP00000380903.1	Q96MS0-1
	ROBO3	ENST00000543966.5	TSL:1	c.86-99C>G		intron	N/A	ENSP00000438799.1	F5H0K7
	ROBO3	ENST00000525448.5	TSL:1	n.1559-99C>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.400 AC: 60666 AN: 151758 Hom.: 13232 Cov.: 31

Gnomad AFR AF: 0.551

Gnomad AMI AF: 0.325

Gnomad AMR AF: 0.292

Gnomad ASJ AF: 0.344

Gnomad EAS AF: 0.0612

Gnomad SAS AF: 0.145

Gnomad FIN AF: 0.385

Gnomad MID AF: 0.449

Gnomad NFE AF: 0.382

Gnomad OTH AF: 0.383

GnomAD4 exome AF: 0.358 AC: 502749 AN: 1404332 Hom.: 95434 Cov.: 26 AF XY: 0.351 AC XY: 244766 AN XY: 696532

African (AFR) AF: 0.559 AC: 17989 AN: 32190

American (AMR) AF: 0.213 AC: 8452 AN: 39686

Ashkenazi Jewish (ASJ) AF: 0.344 AC: 8638 AN: 25088

East Asian (EAS) AF: 0.0650 AC: 2460 AN: 37856

South Asian (SAS) AF: 0.140 AC: 11402 AN: 81732

European-Finnish (FIN) AF: 0.385 AC: 19793 AN: 51352

Middle Eastern (MID) AF: 0.353 AC: 1976 AN: 5594

European-Non Finnish (NFE) AF: 0.384 AC: 411644 AN: 1072530

Other (OTH) AF: 0.350 AC: 20395 AN: 58304

GnomAD4 genome AF: 0.400 AC: 60709 AN: 151876 Hom.: 13242 Cov.: 31 AF XY: 0.390 AC XY: 28995 AN XY: 74254

African (AFR) AF: 0.551 AC: 22793 AN: 41382

American (AMR) AF: 0.291 AC: 4437 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.344 AC: 1191 AN: 3466

East Asian (EAS) AF: 0.0613 AC: 317 AN: 5168

South Asian (SAS) AF: 0.145 AC: 701 AN: 4830

European-Finnish (FIN) AF: 0.385 AC: 4072 AN: 10566

Middle Eastern (MID) AF: 0.452 AC: 133 AN: 294

European-Non Finnish (NFE) AF: 0.382 AC: 25967 AN: 67892

Other (OTH) AF: 0.381 AC: 803 AN: 2110

Alfa AF: 0.391 Hom.: 1608

Bravo AF: 0.403

Asia WGS AF: 0.126 AC: 443 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	8.5
DANN	Benign	0.75
PhyloP100		-0.051
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: rs3802905; hg19: chr11-124749584; COSMIC: COSV60622400; COSMIC: COSV60622400;