rs3862618

Variant names:

• chr11-124872469-G-A
• rs3862618
• NM_022370.4:c.1247G>A

Your query was ambiguous. Multiple possible variants found:

• chr11-124872469-G-A
• chr11-124872469-G-T

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.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. 14/21 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:3
• Conservation: PhyloP100: 0.649
• Publications: 24 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 (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 VariationId 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.

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.1247G>A	p.Arg416His	missense	Exon 8 of 28	NP_071765.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ROBO3	ENST00000397801.6	TSL:1 MANE Select	c.1247G>A	p.Arg416His	missense	Exon 8 of 28	ENSP00000380903.1
	ROBO3	ENST00000538940.5	TSL:5	c.1181G>A	p.Arg394His	missense	Exon 7 of 27	ENSP00000441797.1

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

GnomAD2 exomes AF: 0.129 AC: 32084 AN: 249226 AF XY: 0.132

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 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

African (AFR) AF: 0.0193 AC: 647 AN: 33480

American (AMR) AF: 0.128 AC: 5704 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.108 AC: 2823 AN: 26136

East Asian (EAS) AF: 0.291 AC: 11541 AN: 39698

South Asian (SAS) AF: 0.191 AC: 16437 AN: 86254

European-Finnish (FIN) AF: 0.0849 AC: 4536 AN: 53400

Middle Eastern (MID) AF: 0.151 AC: 868 AN: 5766

European-Non Finnish (NFE) AF: 0.117 AC: 130620 AN: 1111818

Other (OTH) AF: 0.127 AC: 7679 AN: 60374

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

African (AFR) AF: 0.0250 AC: 1038 AN: 41544

American (AMR) AF: 0.114 AC: 1744 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.103 AC: 358 AN: 3472

East Asian (EAS) AF: 0.264 AC: 1362 AN: 5162

South Asian (SAS) AF: 0.188 AC: 902 AN: 4808

European-Finnish (FIN) AF: 0.0823 AC: 871 AN: 10580

Middle Eastern (MID) AF: 0.122 AC: 36 AN: 294

European-Non Finnish (NFE) AF: 0.119 AC: 8059 AN: 68008

Other (OTH) AF: 0.115 AC: 242 AN: 2110

Alfa AF: 0.114 Hom.: 3548

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:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Gaze palsy, familial horizontal, with progressive scoliosis 1 Benign:2

Nov 07, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

not provided Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.9

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
MetaRNN	Benign	0.0032	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L
PhyloP100		0.65
PrimateAI	Benign	0.30	T
PROVEAN	Uncertain	-2.4	N
REVEL	Benign	0.27
Sift	Benign	0.072	T
Sift4G	Uncertain	0.053	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
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: rs3862618; hg19: chr11-124742365; COSMIC: COSV67300458; COSMIC: COSV67300458;