Genetic Variant NM_022370.4:c.1033+67A>G (chr11-124870795-A-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_022370.4(ROBO3):c.1033+67A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.69 in 1,580,152 control chromosomes in the GnomAD database, including 381,313 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.71 ( 39216 hom., cov: 31)

Exomes 𝑓: 0.69 ( 342097 hom. )

Consequence

ROBO3
NM_022370.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.376

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.89).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.825 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ROBO3	NM_022370.4 link	c.1033+67A>G		intron_variant	Intron 6 of 27	ENST00000397801.6	NP_071765.2	Q96MS0-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ROBO3	ENST00000397801.6 link	c.1033+67A>G		intron_variant	Intron 6 of 27	1	NM_022370.4	ENSP00000380903.1		Q96MS0-1
ROBO3	ENST00000538940.5 link	c.967+67A>G		intron_variant	Intron 5 of 26	5		ENSP00000441797.1		F5GWJ5

Frequencies

GnomAD3 genomes

AF:

0.710

AC:

107862

AN:

151920

Hom.:

39183

Cov.:

show subpopulations

Gnomad AFR

AF:

0.832

Gnomad AMI

AF:

0.706

Gnomad AMR

AF:

0.552

Gnomad ASJ

AF:

0.705

Gnomad EAS

AF:

0.399

Gnomad SAS

AF:

0.595

Gnomad FIN

AF:

0.710

Gnomad MID

AF:

0.726

Gnomad NFE

AF:

0.704

Gnomad OTH

AF:

0.706

GnomAD4 exome

AF:

0.688

AC:

982688

AN:

1428112

Hom.:

342097

Cov.:

AF XY:

0.686

AC XY:

485095

AN XY:

706866

show subpopulations

Gnomad4 AFR exome

AF:

0.837

Gnomad4 AMR exome

AF:

0.450

Gnomad4 ASJ exome

AF:

0.695

Gnomad4 EAS exome

AF:

0.447

Gnomad4 SAS exome

AF:

0.598

Gnomad4 FIN exome

AF:

0.700

Gnomad4 NFE exome

AF:

0.707

Gnomad4 OTH exome

AF:

0.686

GnomAD4 genome

AF:

0.710

AC:

107946

AN:

152040

Hom.:

39216

Cov.:

AF XY:

0.704

AC XY:

52300

AN XY:

74330

show subpopulations

Gnomad4 AFR

AF:

0.832

Gnomad4 AMR

AF:

0.551

Gnomad4 ASJ

AF:

0.705

Gnomad4 EAS

AF:

0.398

Gnomad4 SAS

AF:

0.594

Gnomad4 FIN

AF:

0.710

Gnomad4 NFE

AF:

0.704

Gnomad4 OTH

AF:

0.705

Alfa

AF:

0.697

Hom.:

74656

Bravo

AF:

0.701

Asia WGS

AF:

0.551

AC:

1916

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.89

CADD

Benign

9.3

DANN

Benign

0.50

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over