11-124870092-T-C

Position:

• chr11-124870092-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_022370.4(ROBO3):​c.766+24T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.665 in 1,613,568 control chromosomes in the GnomAD database, including 361,989 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.62 (29897 hom., cov: 32)
  • Exomes 𝑓: 0.67 (332092 hom.)
• Consequence: ROBO3 NM_022370.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.320

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 11-124870092-T-C is Benign according to our data. Variant chr11-124870092-T-C is described in ClinVar as [Benign]. Clinvar id is 1327964.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.69 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ROBO3	NM_022370.4	c.766+24T>C		intron_variant		ENST00000397801.6	NP_071765.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ROBO3	ENST00000397801.6	c.766+24T>C		intron_variant		1	NM_022370.4	ENSP00000380903.1
ROBO3	ENST00000538940.5	c.700+24T>C		intron_variant		5		ENSP00000441797.1

Frequencies

GnomAD3 genomes AF: 0.622 AC: 94535 AN: 151898 Hom.: 29906 Cov.: 32

Gnomad AFR AF: 0.569

Gnomad AMI AF: 0.655

Gnomad AMR AF: 0.504

Gnomad ASJ AF: 0.651

Gnomad EAS AF: 0.392

Gnomad SAS AF: 0.581

Gnomad FIN AF: 0.645

Gnomad MID AF: 0.713

Gnomad NFE AF: 0.695

Gnomad OTH AF: 0.648

GnomAD3 exomes AF: 0.599 AC: 149260 AN: 249134 Hom.: 46959 AF XY: 0.608 AC XY: 82216 AN XY: 135136

Gnomad AFR exome AF: 0.568

Gnomad AMR exome AF: 0.390

Gnomad ASJ exome AF: 0.646

Gnomad EAS exome AF: 0.382

Gnomad SAS exome AF: 0.577

Gnomad FIN exome AF: 0.641

Gnomad NFE exome AF: 0.695

Gnomad OTH exome AF: 0.618

GnomAD4 exome AF: 0.669 AC: 978239 AN: 1461552 Hom.: 332092 Cov.: 60 AF XY: 0.668 AC XY: 485770 AN XY: 727018

Gnomad4 AFR exome AF: 0.568

Gnomad4 AMR exome AF: 0.404

Gnomad4 ASJ exome AF: 0.646

Gnomad4 EAS exome AF: 0.443

Gnomad4 SAS exome AF: 0.584

Gnomad4 FIN exome AF: 0.644

Gnomad4 NFE exome AF: 0.700

Gnomad4 OTH exome AF: 0.659

GnomAD4 genome AF: 0.622 AC: 94550 AN: 152016 Hom.: 29897 Cov.: 32 AF XY: 0.615 AC XY: 45696 AN XY: 74282

Gnomad4 AFR AF: 0.568

Gnomad4 AMR AF: 0.503

Gnomad4 ASJ AF: 0.651

Gnomad4 EAS AF: 0.391

Gnomad4 SAS AF: 0.580

Gnomad4 FIN AF: 0.645

Gnomad4 NFE AF: 0.695

Gnomad4 OTH AF: 0.647

Alfa AF: 0.672 Hom.: 50791

Bravo AF: 0.607

Asia WGS AF: 0.518 AC: 1801 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

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

- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	3.0
DANN	Benign	0.39

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs4936957; hg19: chr11-124739988;