rs4606490

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong 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, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.103
• Publications: 10 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 -20 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 VariationId is 1327965.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.709 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.1331-49C>T		intron	N/A	NP_071765.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ROBO3	ENST00000397801.6	TSL:1 MANE Select	c.1331-49C>T		intron	N/A	ENSP00000380903.1	Q96MS0-1
	ROBO3	ENST00000538940.5	TSL:5	c.1265-49C>T		intron	N/A	ENSP00000441797.1	F5GWJ5

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

GnomAD2 exomes AF: 0.491 AC: 55080 AN: 112096 AF XY: 0.490

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 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

African (AFR) AF: 0.724 AC: 20889 AN: 28862

American (AMR) AF: 0.331 AC: 8687 AN: 26228

Ashkenazi Jewish (ASJ) AF: 0.573 AC: 11318 AN: 19762

East Asian (EAS) AF: 0.144 AC: 5139 AN: 35666

South Asian (SAS) AF: 0.390 AC: 25827 AN: 66306

European-Finnish (FIN) AF: 0.598 AC: 27608 AN: 46132

Middle Eastern (MID) AF: 0.542 AC: 1951 AN: 3598

European-Non Finnish (NFE) AF: 0.575 AC: 580397 AN: 1009540

Other (OTH) AF: 0.539 AC: 28889 AN: 53590

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

African (AFR) AF: 0.716 AC: 29681 AN: 41462

American (AMR) AF: 0.419 AC: 6407 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.590 AC: 2047 AN: 3472

East Asian (EAS) AF: 0.116 AC: 598 AN: 5158

South Asian (SAS) AF: 0.389 AC: 1876 AN: 4818

European-Finnish (FIN) AF: 0.608 AC: 6416 AN: 10552

Middle Eastern (MID) AF: 0.578 AC: 170 AN: 294

European-Non Finnish (NFE) AF: 0.569 AC: 38633 AN: 67932

Other (OTH) AF: 0.557 AC: 1175 AN: 2108

Alfa AF: 0.559 Hom.: 33213

Bravo AF: 0.568

Asia WGS AF: 0.288 AC: 1002 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Gaze palsy, familial horizontal, with progressive scoliosis 1 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	3.4
DANN	Benign	0.49
PhyloP100		0.10
Mutation Taster		=100/0	polymorphism (auto)

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; COSMIC: COSV67302769; COSMIC: COSV67302769;