rs4606490

Variant names:

• chr11-124872835-C-A
• rs4606490
• NM_022370.4:c.1331-49C>A

Your query was ambiguous. Multiple possible variants found:

• chr11-124872835-C-A
• chr11-124872835-C-T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_022370.4(ROBO3):​c.1331-49C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000774 in 1,291,502 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 32)
  • Exomes 𝑓: 7.7e-7 (0 hom.)
• Consequence: ROBO3 NM_022370.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.103
• Publications: 0 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: Labcorp Genetics (formerly Invitae), G2P, ClinGen, Genomics England PanelApp

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ROBO3	NM_022370.4	c.1331-49C>A		intron_variant	Intron 8 of 27	ENST00000397801.6	NP_071765.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ROBO3	ENST00000397801.6	c.1331-49C>A		intron_variant	Intron 8 of 27	1	NM_022370.4	ENSP00000380903.1
ROBO3	ENST00000538940.5	c.1265-49C>A		intron_variant	Intron 7 of 26	5		ENSP00000441797.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.74e-7 AC: 1 AN: 1291502 Hom.: 0 Cov.: 21 AF XY: 0.00000158 AC XY: 1 AN XY: 632578

African (AFR) AF: 0.00 AC: 0 AN: 28890

American (AMR) AF: 0.00 AC: 0 AN: 26262

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19770

East Asian (EAS) AF: 0.00 AC: 0 AN: 35678

South Asian (SAS) AF: 0.00 AC: 0 AN: 66392

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46176

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3600

European-Non Finnish (NFE) AF: 9.89e-7 AC: 1 AN: 1011096

Other (OTH) AF: 0.00 AC: 0 AN: 53638

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	2.6
DANN	Benign	0.50
PhyloP100		0.10

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: rs4606490; hg19: chr11-124742731;