3-78606727-G-A

Position:

• chr3-78606727-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_002941.4(ROBO1):​c.4744+6C>T variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000546 in 1,612,482 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0025 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00034 (4 hom.)
• Consequence: ROBO1 NM_002941.4 splice_donor_region, intron
• Scores: Splicing: ADA: 0.00002029
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.864

Genes affected

ROBO1 (HGNC:10249): (roundabout guidance receptor 1) Bilateral symmetric nervous systems have special midline structures that establish a partition between the two mirror image halves. Some axons project toward and across the midline in response to long-range chemoattractants emanating from the midline. The product of this gene is a member of the immunoglobulin gene superfamily and encodes an integral membrane protein that functions in axon guidance and neuronal precursor cell migration. This receptor is activated by SLIT-family proteins, resulting in a repulsive effect on glioma cell guidance in the developing brain. A related gene is located at an adjacent region on chromosome 3. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2009]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 3-78606727-G-A is Benign according to our data. Variant chr3-78606727-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 713549.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-78606727-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00255 (388/152218) while in subpopulation AFR AF= 0.00842 (350/41544). AF 95% confidence interval is 0.0077. There are 3 homozygotes in gnomad4. There are 168 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ROBO1	NM_002941.4	c.4744+6C>T		splice_donor_region_variant, intron_variant		ENST00000464233.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ROBO1	ENST00000464233.6	c.4744+6C>T		splice_donor_region_variant, intron_variant		5	NM_002941.4	P3

Frequencies

GnomAD3 genomes AF: 0.00256 AC: 389 AN: 152100 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00847

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.000745 AC: 185 AN: 248312 Hom.: 0 AF XY: 0.000646 AC XY: 87 AN XY: 134676

Gnomad AFR exome AF: 0.00710

Gnomad AMR exome AF: 0.000899

Gnomad ASJ exome AF: 0.00141

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000204

Gnomad OTH exome AF: 0.00116

GnomAD4 exome AF: 0.000338 AC: 493 AN: 1460264 Hom.: 4 Cov.: 31 AF XY: 0.000302 AC XY: 219 AN XY: 726280

Gnomad4 AFR exome AF: 0.00775

Gnomad4 AMR exome AF: 0.000962

Gnomad4 ASJ exome AF: 0.00115

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000918

Gnomad4 OTH exome AF: 0.000862

GnomAD4 genome AF: 0.00255 AC: 388 AN: 152218 Hom.: 3 Cov.: 32 AF XY: 0.00226 AC XY: 168 AN XY: 74424

Gnomad4 AFR AF: 0.00842

Gnomad4 AMR AF: 0.00105

Gnomad4 ASJ AF: 0.000577

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000176

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00153 Hom.: 1

Bravo AF: 0.00281

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000178

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 08, 2024	- -

ROBO1-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 28, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.51
DANN	Benign	0.51

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000020
dbscSNV1_RF	Benign	0.0040
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: rs115569493; hg19: chr3-78655877;