11-124870092-T-C

Variant names:

• chr11-124870092-T-C
• rs4936957
• NM_022370.4:c.766+24T>C

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.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
• Publications: 13 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: Benign. The variant received -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 VariationId 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.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ROBO3	NM_022370.4	MANE Select	c.766+24T>C		intron	N/A	NP_071765.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ROBO3	ENST00000397801.6	TSL:1 MANE Select	c.766+24T>C		intron	N/A	ENSP00000380903.1
	ROBO3	ENST00000538940.5	TSL:5	c.700+24T>C		intron	N/A	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

GnomAD2 exomes AF: 0.599 AC: 149260 AN: 249134 AF XY: 0.608

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 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

African (AFR) AF: 0.568 AC: 19004 AN: 33476

American (AMR) AF: 0.404 AC: 18081 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.646 AC: 16891 AN: 26134

East Asian (EAS) AF: 0.443 AC: 17580 AN: 39696

South Asian (SAS) AF: 0.584 AC: 50337 AN: 86258

European-Finnish (FIN) AF: 0.644 AC: 34410 AN: 53398

Middle Eastern (MID) AF: 0.688 AC: 3970 AN: 5768

European-Non Finnish (NFE) AF: 0.700 AC: 778200 AN: 1111734

Other (OTH) AF: 0.659 AC: 39766 AN: 60366

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

African (AFR) AF: 0.568 AC: 23564 AN: 41458

American (AMR) AF: 0.503 AC: 7686 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.651 AC: 2256 AN: 3468

East Asian (EAS) AF: 0.391 AC: 2013 AN: 5154

South Asian (SAS) AF: 0.580 AC: 2795 AN: 4820

European-Finnish (FIN) AF: 0.645 AC: 6812 AN: 10566

Middle Eastern (MID) AF: 0.709 AC: 207 AN: 292

European-Non Finnish (NFE) AF: 0.695 AC: 47255 AN: 67960

Other (OTH) AF: 0.647 AC: 1365 AN: 2110

Alfa AF: 0.663 Hom.: 112207

Bravo AF: 0.607

Asia WGS AF: 0.518 AC: 1801 AN: 3478

ClinVar

ClinVar submissions as Germline

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	-0.85
CADD	Benign	3.0
DANN	Benign	0.39
PhyloP100		-0.32
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4936957; hg19: chr11-124739988;