rs121918271

Positions:

• chr11-124875145-G-A
• chr11-124875145-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM2 PM5 BP4_Moderate

The NM_022370.4(ROBO3):​c.2108G>A​(p.Arg703Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000509 in 1,612,512 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R703P) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000049 (0 hom.)
• Consequence: ROBO3 NM_022370.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.35

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-124875145-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2174.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.13751784).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ROBO3	NM_022370.4	c.2108G>A	p.Arg703Gln	missense_variant	14/28	ENST00000397801.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ROBO3	ENST00000397801.6	c.2108G>A	p.Arg703Gln	missense_variant	14/28	1	NM_022370.4	P2
ROBO3	ENST00000538940.5	c.2042G>A	p.Arg681Gln	missense_variant	13/27	5		A2

Frequencies

GnomAD3 genomes AF: 0.0000657 AC: 10 AN: 152224 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000771

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000106 AC: 26 AN: 246146 Hom.: 0 AF XY: 0.000127 AC XY: 17 AN XY: 133684

Gnomad AFR exome AF: 0.0000658

Gnomad AMR exome AF: 0.0000293

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000956

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000629

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000493 AC: 72 AN: 1460170 Hom.: 0 Cov.: 33 AF XY: 0.0000496 AC XY: 36 AN XY: 726284

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000225

Gnomad4 ASJ exome AF: 0.000115

Gnomad4 EAS exome AF: 0.000378

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000432

Gnomad4 OTH exome AF: 0.0000664

GnomAD4 genome AF: 0.0000656 AC: 10 AN: 152342 Hom.: 0 Cov.: 32 AF XY: 0.0000537 AC XY: 4 AN XY: 74490

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000773

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000113 Hom.: 0

Bravo AF: 0.0000945

ESP6500AA AF: 0.000249 AC: 1

ESP6500EA AF: 0.000361 AC: 3

ExAC AF: 0.000107 AC: 13

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	22
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.14	T;.
Eigen	Benign	0.12
Eigen_PC	Benign	0.097
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.72	T;T
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.14	T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Uncertain	2.6	M;.
MutationTaster	Benign	0.75	N;N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-2.0	N;N
REVEL	Uncertain	0.33
Sift	Benign	0.11	T;T
Sift4G	Uncertain	0.053	T;T
Polyphen		0.98	D;.
Vest4		0.30
MVP		0.71
MPC		0.13
ClinPred		0.28	T
GERP RS		2.3
Varity_R		0.19
gMVP		0.57

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs121918271; hg19: chr11-124745041;