rs4606490

Positions:

• chr11-124872835-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_022370.4(ROBO3):​c.1331-49C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.554 in 1,441,680 control chromosomes in the GnomAD database, including 228,409 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.58 (26556 hom., cov: 32)
  • Exomes 𝑓: 0.55 (201853 hom.)
• Consequence: ROBO3 NM_022370.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.103

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 11-124872835-C-T is Benign according to our data. Variant chr11-124872835-C-T is described in ClinVar as [Benign]. Clinvar id is 1327965.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.709 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ROBO3	NM_022370.4	c.1331-49C>T		intron_variant		ENST00000397801.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ROBO3	ENST00000397801.6	c.1331-49C>T		intron_variant		1	NM_022370.4	P2
ROBO3	ENST00000538940.5	c.1265-49C>T		intron_variant		5		A2

Frequencies

GnomAD3 genomes AF: 0.576 AC: 87455 AN: 151878 Hom.: 26540 Cov.: 32

Gnomad AFR AF: 0.716

Gnomad AMI AF: 0.549

Gnomad AMR AF: 0.420

Gnomad ASJ AF: 0.590

Gnomad EAS AF: 0.116

Gnomad SAS AF: 0.391

Gnomad FIN AF: 0.608

Gnomad MID AF: 0.589

Gnomad NFE AF: 0.569

Gnomad OTH AF: 0.564

GnomAD3 exomes AF: 0.491 AC: 55080 AN: 112096 Hom.: 15232 AF XY: 0.490 AC XY: 28028 AN XY: 57236

Gnomad AFR exome AF: 0.734

Gnomad AMR exome AF: 0.311

Gnomad ASJ exome AF: 0.574

Gnomad EAS exome AF: 0.120

Gnomad SAS exome AF: 0.386

Gnomad FIN exome AF: 0.602

Gnomad NFE exome AF: 0.582

Gnomad OTH exome AF: 0.501

GnomAD4 exome AF: 0.551 AC: 710705 AN: 1289684 Hom.: 201853 Cov.: 21 AF XY: 0.547 AC XY: 345755 AN XY: 631700

Gnomad4 AFR exome AF: 0.724

Gnomad4 AMR exome AF: 0.331

Gnomad4 ASJ exome AF: 0.573

Gnomad4 EAS exome AF: 0.144

Gnomad4 SAS exome AF: 0.390

Gnomad4 FIN exome AF: 0.598

Gnomad4 NFE exome AF: 0.575

Gnomad4 OTH exome AF: 0.539

GnomAD4 genome AF: 0.576 AC: 87504 AN: 151996 Hom.: 26556 Cov.: 32 AF XY: 0.568 AC XY: 42205 AN XY: 74286

Gnomad4 AFR AF: 0.716

Gnomad4 AMR AF: 0.419

Gnomad4 ASJ AF: 0.590

Gnomad4 EAS AF: 0.116

Gnomad4 SAS AF: 0.389

Gnomad4 FIN AF: 0.608

Gnomad4 NFE AF: 0.569

Gnomad4 OTH AF: 0.557

Alfa AF: 0.556 Hom.: 27624

Bravo AF: 0.568

Asia WGS AF: 0.288 AC: 1002 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Gaze palsy, familial horizontal, with progressive scoliosis 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Nov 07, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	3.4
DANN	Benign	0.49

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

Publications

LitVar

Other links and lift over

dbSNP: rs4606490; hg19: chr11-124742731; COSMIC: COSV67302769; COSMIC: COSV67302769;