rs3862618

chr11-124872469-G-Achr11-124872469-G-T

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.1247G>A(p.Arg416His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.121 in 1,613,832 control chromosomes in the GnomAD database, including 13,613 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.096 (978 hom., cov: 32)
  • Exomes 𝑓: 0.12 (12635 hom.)
• Consequence: ROBO3 NM_022370.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.649

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 (MetaRNN=0.0032360852).
• BP6: Variant 11-124872469-G-A is Benign according to our data. Variant chr11-124872469-G-A is described in ClinVar as [Benign]. Clinvar id is 303235.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.252 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ROBO3	NM_022370.4	c.1247G>A	p.Arg416His	missense_variant	8/28	ENST00000397801.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ROBO3	ENST00000397801.6	c.1247G>A	p.Arg416His	missense_variant	8/28	1	NM_022370.4	P2
ROBO3	ENST00000538940.5	c.1181G>A	p.Arg394His	missense_variant	7/27	5		A2

Frequencies

GnomAD3 genomes AF: 0.0965 AC: 14673 AN: 152066 Hom.: 979 Cov.: 32

Gnomad AFR AF: 0.0250

Gnomad AMI AF: 0.0669

Gnomad AMR AF: 0.114

Gnomad ASJ AF: 0.103

Gnomad EAS AF: 0.265

Gnomad SAS AF: 0.188

Gnomad FIN AF: 0.0823

Gnomad MID AF: 0.120

Gnomad NFE AF: 0.118

Gnomad OTH AF: 0.110

GnomAD3 exomes AF: 0.129 AC: 32084 AN: 249226 Hom.: 2526 AF XY: 0.132 AC XY: 17839 AN XY: 135208

Gnomad AFR exome AF: 0.0211

Gnomad AMR exome AF: 0.132

Gnomad ASJ exome AF: 0.107

Gnomad EAS exome AF: 0.254

Gnomad SAS exome AF: 0.188

Gnomad FIN exome AF: 0.0831

Gnomad NFE exome AF: 0.117

Gnomad OTH exome AF: 0.123

GnomAD4 exome AF: 0.124 AC: 180855 AN: 1461648 Hom.: 12635 Cov.: 32 AF XY: 0.126 AC XY: 91710 AN XY: 727106

Gnomad4 AFR exome AF: 0.0193

Gnomad4 AMR exome AF: 0.128

Gnomad4 ASJ exome AF: 0.108

Gnomad4 EAS exome AF: 0.291

Gnomad4 SAS exome AF: 0.191

Gnomad4 FIN exome AF: 0.0849

Gnomad4 NFE exome AF: 0.117

Gnomad4 OTH exome AF: 0.127

GnomAD4 genome AF: 0.0964 AC: 14673 AN: 152184 Hom.: 978 Cov.: 32 AF XY: 0.0981 AC XY: 7298 AN XY: 74400

Gnomad4 AFR AF: 0.0250

Gnomad4 AMR AF: 0.114

Gnomad4 ASJ AF: 0.103

Gnomad4 EAS AF: 0.264

Gnomad4 SAS AF: 0.188

Gnomad4 FIN AF: 0.0823

Gnomad4 NFE AF: 0.119

Gnomad4 OTH AF: 0.115

Alfa AF: 0.120 Hom.: 2673

Bravo AF: 0.0930

TwinsUK AF: 0.118 AC: 437

ALSPAC AF: 0.116 AC: 448

ESP6500AA AF: 0.0219 AC: 93

ESP6500EA AF: 0.110 AC: 932

ExAC AF: 0.127 AC: 15329

Asia WGS AF: 0.237 AC: 825 AN: 3478

EpiCase AF: 0.122

EpiControl AF: 0.124

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
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.53
Cadd	Benign	16
Dann	Uncertain	0.99
DEOGEN2	Benign	0.29	T;.
Eigen	Benign	-0.063
Eigen_PC	Benign	-0.067
FATHMM_MKL	Benign	0.65	D
LIST_S2	Uncertain	0.86	D;D
MetaRNN	Benign	0.0032	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L;.
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.30	T
PROVEAN	Uncertain	-2.4	N;N
REVEL	Benign	0.27
Sift	Benign	0.072	T;T
Sift4G	Uncertain	0.053	T;T
Polyphen		0.73	P;.
Vest4		0.034
MPC		0.11
ClinPred		0.011	T
GERP RS		3.8
Varity_R		0.079
gMVP		0.24

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: rs3862618; hg19: chr11-124742365; COSMIC: COSV67300458; COSMIC: COSV67300458;