11-124879688-C-G

Position:

• chr11-124879688-C-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000397801.6(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 ENST00000397801.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0510

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]

ACMG classification

Verdict is Benign. Variant got -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ROBO3	NM_022370.4	c.3797-99C>G		intron_variant		ENST00000397801.6	NP_071765.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ROBO3	ENST00000397801.6	c.3797-99C>G		intron_variant		1	NM_022370.4	ENSP00000380903	P2

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

Gnomad4 AFR exome AF: 0.559

Gnomad4 AMR exome AF: 0.213

Gnomad4 ASJ exome AF: 0.344

Gnomad4 EAS exome AF: 0.0650

Gnomad4 SAS exome AF: 0.140

Gnomad4 FIN exome AF: 0.385

Gnomad4 NFE exome AF: 0.384

Gnomad4 OTH exome AF: 0.350

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

Gnomad4 AFR AF: 0.551

Gnomad4 AMR AF: 0.291

Gnomad4 ASJ AF: 0.344

Gnomad4 EAS AF: 0.0613

Gnomad4 SAS AF: 0.145

Gnomad4 FIN AF: 0.385

Gnomad4 NFE AF: 0.382

Gnomad4 OTH AF: 0.381

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 v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	8.5
DANN	Benign	0.75

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

Publications

LitVar

Other links and lift over

dbSNP: rs3802905; hg19: chr11-124749584; COSMIC: COSV60622400; COSMIC: COSV60622400;