11-124869436-A-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.488-14A>C variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.503 in 1,135,930 control chromosomes in the GnomAD database, including 177,320 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.56 (24063 hom., cov: 25)
  • Exomes 𝑓: 0.49 (153257 hom.)
• Consequence: ROBO3 NM_022370.4 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.44

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=-0.84).
• BP6: Variant 11-124869436-A-C is Benign according to our data. Variant chr11-124869436-A-C is described in ClinVar as [Benign]. Clinvar id is 303222.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.665 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ROBO3	NM_022370.4	c.488-14A>C		splice_polypyrimidine_tract_variant, intron_variant		ENST00000397801.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ROBO3	ENST00000397801.6	c.488-14A>C		splice_polypyrimidine_tract_variant, intron_variant		1	NM_022370.4	P2
ROBO3	ENST00000538940.5	c.422-14A>C		splice_polypyrimidine_tract_variant, intron_variant		5		A2

Frequencies

GnomAD3 genomes AF: 0.564 AC: 80485 AN: 142658 Hom.: 24046 Cov.: 25

Gnomad AFR AF: 0.672

Gnomad AMI AF: 0.707

Gnomad AMR AF: 0.510

Gnomad ASJ AF: 0.604

Gnomad EAS AF: 0.0607

Gnomad SAS AF: 0.406

Gnomad FIN AF: 0.470

Gnomad MID AF: 0.643

Gnomad NFE AF: 0.574

Gnomad OTH AF: 0.577

GnomAD3 exomes AF: 0.474 AC: 73556 AN: 155264 Hom.: 19683 AF XY: 0.474 AC XY: 39312 AN XY: 82928

Gnomad AFR exome AF: 0.672

Gnomad AMR exome AF: 0.410

Gnomad ASJ exome AF: 0.608

Gnomad EAS exome AF: 0.0533

Gnomad SAS exome AF: 0.415

Gnomad FIN exome AF: 0.502

Gnomad NFE exome AF: 0.556

Gnomad OTH exome AF: 0.525

GnomAD4 exome AF: 0.494 AC: 491004 AN: 993192 Hom.: 153257 Cov.: 30 AF XY: 0.496 AC XY: 249153 AN XY: 502656

Gnomad4 AFR exome AF: 0.670

Gnomad4 AMR exome AF: 0.432

Gnomad4 ASJ exome AF: 0.597

Gnomad4 EAS exome AF: 0.0459

Gnomad4 SAS exome AF: 0.398

Gnomad4 FIN exome AF: 0.511

Gnomad4 NFE exome AF: 0.518

Gnomad4 OTH exome AF: 0.506

GnomAD4 genome AF: 0.564 AC: 80541 AN: 142738 Hom.: 24063 Cov.: 25 AF XY: 0.553 AC XY: 38372 AN XY: 69340

Gnomad4 AFR AF: 0.672

Gnomad4 AMR AF: 0.510

Gnomad4 ASJ AF: 0.604

Gnomad4 EAS AF: 0.0603

Gnomad4 SAS AF: 0.408

Gnomad4 FIN AF: 0.470

Gnomad4 NFE AF: 0.574

Gnomad4 OTH AF: 0.569

Alfa AF: 0.476 Hom.: 1660

Bravo AF: 0.581

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:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
Cadd	Benign	0.38
Dann	Benign	0.58

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

Publications

LitVar

Other links and lift over

dbSNP: rs11219820; hg19: chr11-124739332; COSMIC: COSV67301610;