3-78606773-T-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_002941.4(ROBO1):c.4704A>C(p.Ala1568=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0144 in 1,613,932 control chromosomes in the GnomAD database, including 234 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (24 hom., cov: 32)
  • Exomes 𝑓: 0.014 (210 hom.)
• Consequence: ROBO1 NM_002941.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.544

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 3-78606773-T-G is Benign according to our data. Variant chr3-78606773-T-G is described in ClinVar as [Benign]. Clinvar id is 1529664.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.544 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0155 (2360/152260) while in subpopulation AFR AF= 0.0209 (867/41554). AF 95% confidence interval is 0.0197. There are 24 homozygotes in gnomad4. There are 1135 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 24 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ROBO1	NM_002941.4	c.4704A>C	p.Ala1568=	synonymous_variant	29/31	ENST00000464233.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ROBO1	ENST00000464233.6	c.4704A>C	p.Ala1568=	synonymous_variant	29/31	5	NM_002941.4	P3

Frequencies

GnomAD3 genomes AF: 0.0155 AC: 2355 AN: 152142 Hom.: 24 Cov.: 32

Gnomad AFR AF: 0.0209

Gnomad AMI AF: 0.0296

Gnomad AMR AF: 0.0132

Gnomad ASJ AF: 0.0153

Gnomad EAS AF: 0.0160

Gnomad SAS AF: 0.00807

Gnomad FIN AF: 0.00688

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0144

Gnomad OTH AF: 0.0143

GnomAD3 exomes AF: 0.0127 AC: 3153 AN: 249230 Hom.: 24 AF XY: 0.0128 AC XY: 1736 AN XY: 135202

Gnomad AFR exome AF: 0.0230

Gnomad AMR exome AF: 0.00985

Gnomad ASJ exome AF: 0.0141

Gnomad EAS exome AF: 0.00846

Gnomad SAS exome AF: 0.00712

Gnomad FIN exome AF: 0.00832

Gnomad NFE exome AF: 0.0148

Gnomad OTH exome AF: 0.0149

GnomAD4 exome AF: 0.0143 AC: 20876 AN: 1461672 Hom.: 210 Cov.: 32 AF XY: 0.0141 AC XY: 10220 AN XY: 727114

Gnomad4 AFR exome AF: 0.0243

Gnomad4 AMR exome AF: 0.0108

Gnomad4 ASJ exome AF: 0.0140

Gnomad4 EAS exome AF: 0.0356

Gnomad4 SAS exome AF: 0.00722

Gnomad4 FIN exome AF: 0.00803

Gnomad4 NFE exome AF: 0.0141

Gnomad4 OTH exome AF: 0.0156

GnomAD4 genome AF: 0.0155 AC: 2360 AN: 152260 Hom.: 24 Cov.: 32 AF XY: 0.0152 AC XY: 1135 AN XY: 74460

Gnomad4 AFR AF: 0.0209

Gnomad4 AMR AF: 0.0132

Gnomad4 ASJ AF: 0.0153

Gnomad4 EAS AF: 0.0161

Gnomad4 SAS AF: 0.00808

Gnomad4 FIN AF: 0.00688

Gnomad4 NFE AF: 0.0144

Gnomad4 OTH AF: 0.0161

Alfa AF: 0.0141 Hom.: 10

Bravo AF: 0.0163

Asia WGS AF: 0.0170 AC: 58 AN: 3478

EpiCase AF: 0.0174

EpiControl AF: 0.0167

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

ROBO1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 12, 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). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 16, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
Cadd	Benign	1.7
Dann	Benign	0.47

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

Other links and lift over

dbSNP: rs35148826; hg19: chr3-78655923;