rs1027832

Positions:

• chr3-78614806-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002941.4(ROBO1):​c.4283-6C>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.406 in 1,543,268 control chromosomes in the GnomAD database, including 129,111 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.37 (11037 hom., cov: 29)
  • Exomes 𝑓: 0.41 (118074 hom.)
• Consequence: ROBO1 NM_002941.4 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00003322
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.360

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 3-78614806-G-A is Benign according to our data. Variant chr3-78614806-G-A is described in ClinVar as [Benign]. Clinvar id is 1642377.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.491 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ROBO1	NM_002941.4	c.4283-6C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000464233.6	NP_002932.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ROBO1	ENST00000464233.6	c.4283-6C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5	NM_002941.4	ENSP00000420321	P3

Frequencies

GnomAD3 genomes AF: 0.373 AC: 54878 AN: 147056 Hom.: 11036 Cov.: 29

Gnomad AFR AF: 0.212

Gnomad AMI AF: 0.549

Gnomad AMR AF: 0.500

Gnomad ASJ AF: 0.445

Gnomad EAS AF: 0.326

Gnomad SAS AF: 0.434

Gnomad FIN AF: 0.487

Gnomad MID AF: 0.424

Gnomad NFE AF: 0.416

Gnomad OTH AF: 0.400

GnomAD3 exomes AF: 0.454 AC: 80681 AN: 177654 Hom.: 17536 AF XY: 0.453 AC XY: 43496 AN XY: 96102

Gnomad AFR exome AF: 0.244

Gnomad AMR exome AF: 0.596

Gnomad ASJ exome AF: 0.470

Gnomad EAS exome AF: 0.360

Gnomad SAS exome AF: 0.458

Gnomad FIN exome AF: 0.493

Gnomad NFE exome AF: 0.441

Gnomad OTH exome AF: 0.450

GnomAD4 exome AF: 0.410 AC: 571734 AN: 1396124 Hom.: 118074 Cov.: 34 AF XY: 0.411 AC XY: 284078 AN XY: 691988

Gnomad4 AFR exome AF: 0.205

Gnomad4 AMR exome AF: 0.562

Gnomad4 ASJ exome AF: 0.451

Gnomad4 EAS exome AF: 0.291

Gnomad4 SAS exome AF: 0.432

Gnomad4 FIN exome AF: 0.465

Gnomad4 NFE exome AF: 0.410

Gnomad4 OTH exome AF: 0.406

GnomAD4 genome AF: 0.373 AC: 54888 AN: 147144 Hom.: 11037 Cov.: 29 AF XY: 0.380 AC XY: 27149 AN XY: 71536

Gnomad4 AFR AF: 0.212

Gnomad4 AMR AF: 0.501

Gnomad4 ASJ AF: 0.445

Gnomad4 EAS AF: 0.325

Gnomad4 SAS AF: 0.434

Gnomad4 FIN AF: 0.487

Gnomad4 NFE AF: 0.416

Gnomad4 OTH AF: 0.399

Alfa AF: 0.409 Hom.: 25242

Bravo AF: 0.361

Asia WGS AF: 0.366 AC: 1260 AN: 3442

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	1.2
DANN	Benign	0.44

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000033
dbscSNV1_RF	Benign	0.012
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: rs1027832; hg19: chr3-78663956;