Variant chr11-124872835-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_022370.4(ROBO3):c.1331-49C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.554 in 1,441,680 control chromosomes in the GnomAD database, including 228,409 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.58 ( 26556 hom., cov: 32)

Exomes 𝑓: 0.55 ( 201853 hom. )

Consequence

ROBO3
NM_022370.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.103

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.81).

BP6

Variant 11-124872835-C-T is Benign according to our data. Variant chr11-124872835-C-T is described in ClinVar as [Benign]. Clinvar id is 1327965.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.709 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ROBO3	NM_022370.4 linkuse as main transcript	c.1331-49C>T		intron_variant		ENST00000397801.6	NP_071765.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ROBO3	ENST00000397801.6 linkuse as main transcript	c.1331-49C>T		intron_variant		1	NM_022370.4	ENSP00000380903	P2	Q96MS0-1
ROBO3	ENST00000538940.5 linkuse as main transcript	c.1265-49C>T		intron_variant		5		ENSP00000441797	A2

Frequencies

GnomAD3 genomes

AF:

0.576

AC:

87455

AN:

151878

Hom.:

26540

Cov.:

show subpopulations

Gnomad AFR

AF:

0.716

Gnomad AMI

AF:

0.549

Gnomad AMR

AF:

0.420

Gnomad ASJ

AF:

0.590

Gnomad EAS

AF:

0.116

Gnomad SAS

AF:

0.391

Gnomad FIN

AF:

0.608

Gnomad MID

AF:

0.589

Gnomad NFE

AF:

0.569

Gnomad OTH

AF:

0.564

GnomAD3 exomes

AF:

0.491

AC:

55080

AN:

112096

Hom.:

15232

AF XY:

0.490

AC XY:

28028

AN XY:

57236

show subpopulations

Gnomad AFR exome

AF:

0.734

Gnomad AMR exome

AF:

0.311

Gnomad ASJ exome

AF:

0.574

Gnomad EAS exome

AF:

0.120

Gnomad SAS exome

AF:

0.386

Gnomad FIN exome

AF:

0.602

Gnomad NFE exome

AF:

0.582

Gnomad OTH exome

AF:

0.501

GnomAD4 exome

AF:

0.551

AC:

710705

AN:

1289684

Hom.:

201853

Cov.:

AF XY:

0.547

AC XY:

345755

AN XY:

631700

show subpopulations

Gnomad4 AFR exome

AF:

0.724

Gnomad4 AMR exome

AF:

0.331

Gnomad4 ASJ exome

AF:

0.573

Gnomad4 EAS exome

AF:

0.144

Gnomad4 SAS exome

AF:

0.390

Gnomad4 FIN exome

AF:

0.598

Gnomad4 NFE exome

AF:

0.575

Gnomad4 OTH exome

AF:

0.539

GnomAD4 genome

AF:

0.576

AC:

87504

AN:

151996

Hom.:

26556

Cov.:

AF XY:

0.568

AC XY:

42205

AN XY:

74286

show subpopulations

Gnomad4 AFR

AF:

0.716

Gnomad4 AMR

AF:

0.419

Gnomad4 ASJ

AF:

0.590

Gnomad4 EAS

AF:

0.116

Gnomad4 SAS

AF:

0.389

Gnomad4 FIN

AF:

0.608

Gnomad4 NFE

AF:

0.569

Gnomad4 OTH

AF:

0.557

Alfa

AF:

0.556

Hom.:

27624

Bravo

AF:

0.568

Asia WGS

AF:

0.288

AC:

1002

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Gaze palsy, familial horizontal, with progressive scoliosis 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Nov 07, 2021

- -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

3.4

DANN

Benign

0.49

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

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over