rs185584218

Variant names:

• chr11-124865458-G-C
• rs185584218
• NM_022370.4:c.-120G>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Moderate BP6_Moderate BS1 BS2

The NM_022370.4(ROBO3):​c.-120G>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00177 in 1,003,294 control chromosomes in the GnomAD database, including 28 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0075 (15 hom., cov: 33)
  • Exomes 𝑓: 0.00074 (13 hom.)
• Consequence: ROBO3 NM_022370.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.277
• Publications: 2 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), Genomics England PanelApp, ClinGen, G2P

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.41).
• BP6: Variant 11-124865458-G-C is Benign according to our data. Variant chr11-124865458-G-C is described in ClinVar as Benign. ClinVar VariationId is 303216.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00748 (1138/152218) while in subpopulation AFR AF = 0.0257 (1069/41548). AF 95% confidence interval is 0.0244. There are 15 homozygotes in GnomAd4. There are 537 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 15 AR gene

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.-120G>C		5_prime_UTR	Exon 1 of 28	NP_071765.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ROBO3	ENST00000397801.6	TSL:1 MANE Select	c.-120G>C		5_prime_UTR	Exon 1 of 28	ENSP00000380903.1	Q96MS0-1

Frequencies

GnomAD3 genomes AF: 0.00746 AC: 1135 AN: 152100 Hom.: 15 Cov.: 33

Gnomad AFR AF: 0.0257

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00308

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00671

GnomAD4 exome AF: 0.000745 AC: 634 AN: 851076 Hom.: 13 Cov.: 11 AF XY: 0.000666 AC XY: 286 AN XY: 429138

African (AFR) AF: 0.0247 AC: 498 AN: 20166

American (AMR) AF: 0.00134 AC: 33 AN: 24718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17588

East Asian (EAS) AF: 0.00 AC: 0 AN: 32742

South Asian (SAS) AF: 0.0000519 AC: 3 AN: 57748

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32106

Middle Eastern (MID) AF: 0.000711 AC: 2 AN: 2812

European-Non Finnish (NFE) AF: 0.0000305 AC: 19 AN: 623934

Other (OTH) AF: 0.00201 AC: 79 AN: 39262

GnomAD4 genome AF: 0.00748 AC: 1138 AN: 152218 Hom.: 15 Cov.: 33 AF XY: 0.00722 AC XY: 537 AN XY: 74428

African (AFR) AF: 0.0257 AC: 1069 AN: 41548

American (AMR) AF: 0.00301 AC: 46 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5152

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 67996

Other (OTH) AF: 0.00664 AC: 14 AN: 2108

Alfa AF: 0.00680 Hom.: 1

Bravo AF: 0.00852

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Gaze palsy, familial horizontal, with progressive scoliosis 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
CADD	Benign	19
DANN	Benign	0.89
PhyloP100		0.28
PromoterAI		-0.043	Neutral
Mutation Taster		=300/0	polymorphism

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: rs185584218; hg19: chr11-124735354;