3-78688812-G-A

Variant names:

• chr3-78688812-G-A
• rs967454
• NM_002941.4:c.1046-40C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002941.4(ROBO1):​c.1046-40C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.459 in 1,570,346 control chromosomes in the GnomAD database, including 173,118 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.37 (13055 hom., cov: 32)
  • Exomes 𝑓: 0.47 (160063 hom.)
• Consequence: ROBO1 NM_002941.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.939
• Publications: 11 publications found

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 Gene-Disease associations (from GenCC):

• neurooculorenal syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• pituitary hormone deficiency, combined or isolated, 8

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• pituitary stalk interruption syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.489 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002941.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ROBO1	NM_002941.4	MANE Select	c.1046-40C>T		intron	N/A	NP_002932.1
	ROBO1	NM_133631.4		c.938-40C>T		intron	N/A	NP_598334.2
	ROBO1	NM_001145845.2		c.938-40C>T		intron	N/A	NP_001139317.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ROBO1	ENST00000464233.6	TSL:5 MANE Select	c.1046-40C>T		intron	N/A	ENSP00000420321.1
	ROBO1	ENST00000495273.5	TSL:1	c.938-40C>T		intron	N/A	ENSP00000420637.1
	ROBO1	ENST00000467549.5	TSL:1	c.938-40C>T		intron	N/A	ENSP00000417992.1

Frequencies

GnomAD3 genomes AF: 0.374 AC: 56836 AN: 151874 Hom.: 13069 Cov.: 32

Gnomad AFR AF: 0.107

Gnomad AMI AF: 0.568

Gnomad AMR AF: 0.462

Gnomad ASJ AF: 0.569

Gnomad EAS AF: 0.220

Gnomad SAS AF: 0.456

Gnomad FIN AF: 0.469

Gnomad MID AF: 0.548

Gnomad NFE AF: 0.494

Gnomad OTH AF: 0.412

GnomAD2 exomes AF: 0.442 AC: 88730 AN: 200694 AF XY: 0.447

Gnomad AFR exome AF: 0.101

Gnomad AMR exome AF: 0.468

Gnomad ASJ exome AF: 0.565

Gnomad EAS exome AF: 0.214

Gnomad FIN exome AF: 0.474

Gnomad NFE exome AF: 0.492

Gnomad OTH exome AF: 0.459

GnomAD4 exome AF: 0.468 AC: 663863 AN: 1418354 Hom.: 160063 Cov.: 26 AF XY: 0.470 AC XY: 330349 AN XY: 702638

African (AFR) AF: 0.0929 AC: 3014 AN: 32432

American (AMR) AF: 0.458 AC: 17838 AN: 38928

Ashkenazi Jewish (ASJ) AF: 0.564 AC: 14079 AN: 24944

East Asian (EAS) AF: 0.215 AC: 8271 AN: 38388

South Asian (SAS) AF: 0.466 AC: 37297 AN: 80066

European-Finnish (FIN) AF: 0.470 AC: 24153 AN: 51378

Middle Eastern (MID) AF: 0.502 AC: 2843 AN: 5658

European-Non Finnish (NFE) AF: 0.487 AC: 530050 AN: 1087802

Other (OTH) AF: 0.448 AC: 26318 AN: 58758

GnomAD4 genome AF: 0.374 AC: 56806 AN: 151992 Hom.: 13055 Cov.: 32 AF XY: 0.378 AC XY: 28038 AN XY: 74270

African (AFR) AF: 0.107 AC: 4436 AN: 41506

American (AMR) AF: 0.462 AC: 7051 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.569 AC: 1972 AN: 3466

East Asian (EAS) AF: 0.219 AC: 1133 AN: 5172

South Asian (SAS) AF: 0.454 AC: 2182 AN: 4802

European-Finnish (FIN) AF: 0.469 AC: 4946 AN: 10538

Middle Eastern (MID) AF: 0.541 AC: 158 AN: 292

European-Non Finnish (NFE) AF: 0.494 AC: 33549 AN: 67940

Other (OTH) AF: 0.408 AC: 862 AN: 2114

Alfa AF: 0.436 Hom.: 3449

Bravo AF: 0.356

Asia WGS AF: 0.301 AC: 1048 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.75
DANN	Benign	0.68
PhyloP100		-0.94
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs967454; hg19: chr3-78737962; COSMIC: COSV71394114; COSMIC: COSV71394114;