rs7636043

Positions:

• chr3-78627317-A-G

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.3875+4T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.966 in 1,611,048 control chromosomes in the GnomAD database, including 751,405 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 0.97 (71634 hom., cov: 32)
  • Exomes 𝑓: 0.97 (679771 hom.)
• Consequence: ROBO1 NM_002941.4 splice_region, intron
• Scores: Splicing: ADA: 0.00001445
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.02

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]

ROBO1 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 3-78627317-A-G is Benign according to our data. Variant chr3-78627317-A-G is described in ClinVar as [Benign]. Clinvar id is 1542355.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.97 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ROBO1	NM_002941.4	c.3875+4T>C		splice_region_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.3875+4T>C		splice_region_variant, intron_variant		5	NM_002941.4	ENSP00000420321.1

Frequencies

GnomAD3 genomes AF: 0.970 AC: 147570 AN: 152164 Hom.: 71577 Cov.: 32

Gnomad AFR AF: 0.978

Gnomad AMI AF: 0.992

Gnomad AMR AF: 0.976

Gnomad ASJ AF: 0.982

Gnomad EAS AF: 0.991

Gnomad SAS AF: 0.925

Gnomad FIN AF: 0.966

Gnomad MID AF: 0.965

Gnomad NFE AF: 0.964

Gnomad OTH AF: 0.976

GnomAD3 exomes AF: 0.966 AC: 236571 AN: 244810 Hom.: 114342 AF XY: 0.964 AC XY: 127853 AN XY: 132652

Gnomad AFR exome AF: 0.979

Gnomad AMR exome AF: 0.984

Gnomad ASJ exome AF: 0.982

Gnomad EAS exome AF: 0.992

Gnomad SAS exome AF: 0.930

Gnomad FIN exome AF: 0.964

Gnomad NFE exome AF: 0.964

Gnomad OTH exome AF: 0.967

GnomAD4 exome AF: 0.965 AC: 1408085 AN: 1458766 Hom.: 679771 Cov.: 44 AF XY: 0.964 AC XY: 699262 AN XY: 725310

Gnomad4 AFR exome AF: 0.981

Gnomad4 AMR exome AF: 0.984

Gnomad4 ASJ exome AF: 0.982

Gnomad4 EAS exome AF: 0.996

Gnomad4 SAS exome AF: 0.931

Gnomad4 FIN exome AF: 0.964

Gnomad4 NFE exome AF: 0.965

Gnomad4 OTH exome AF: 0.967

GnomAD4 genome AF: 0.970 AC: 147686 AN: 152282 Hom.: 71634 Cov.: 32 AF XY: 0.970 AC XY: 72187 AN XY: 74454

Gnomad4 AFR AF: 0.978

Gnomad4 AMR AF: 0.976

Gnomad4 ASJ AF: 0.982

Gnomad4 EAS AF: 0.991

Gnomad4 SAS AF: 0.925

Gnomad4 FIN AF: 0.966

Gnomad4 NFE AF: 0.964

Gnomad4 OTH AF: 0.975

Alfa AF: 0.967 Hom.: 45133

Bravo AF: 0.973

Asia WGS AF: 0.956 AC: 3325 AN: 3478

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	-0.89
CADD	Benign	0.0010
DANN	Benign	0.46
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000014
dbscSNV1_RF	Benign	0.0
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: rs7636043; hg19: chr3-78676467;