NM_002941.4:c.499+66231G>T

Variant names:

• chr3-78872370-C-A
• rs12495133
• NM_002941.4:c.499+66231G>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.499+66231G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.312 in 152,102 control chromosomes in the GnomAD database, including 8,732 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 0.31 (8732 hom., cov: 32)
• Consequence: ROBO1 NM_002941.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.19
• Publications: 9 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=-0.76).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.46 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.499+66231G>T		intron	N/A	NP_002932.1
	ROBO1	NM_133631.4		c.382+66231G>T		intron	N/A	NP_598334.2
	ROBO1	NM_001145845.2		c.382+66231G>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.499+66231G>T		intron	N/A	ENSP00000420321.1
	ROBO1	ENST00000495273.5	TSL:1	c.382+66231G>T		intron	N/A	ENSP00000420637.1
	ROBO1	ENST00000467549.5	TSL:1	c.382+66231G>T		intron	N/A	ENSP00000417992.1

Frequencies

GnomAD3 genomes AF: 0.312 AC: 47493 AN: 151984 Hom.: 8736 Cov.: 32

Gnomad AFR AF: 0.108

Gnomad AMI AF: 0.464

Gnomad AMR AF: 0.393

Gnomad ASJ AF: 0.456

Gnomad EAS AF: 0.300

Gnomad SAS AF: 0.477

Gnomad FIN AF: 0.383

Gnomad MID AF: 0.433

Gnomad NFE AF: 0.387

Gnomad OTH AF: 0.326

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.312 AC: 47486 AN: 152102 Hom.: 8732 Cov.: 32 AF XY: 0.318 AC XY: 23650 AN XY: 74344

African (AFR) AF: 0.108 AC: 4469 AN: 41538

American (AMR) AF: 0.393 AC: 5996 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.456 AC: 1581 AN: 3470

East Asian (EAS) AF: 0.301 AC: 1554 AN: 5164

South Asian (SAS) AF: 0.477 AC: 2299 AN: 4824

European-Finnish (FIN) AF: 0.383 AC: 4050 AN: 10570

Middle Eastern (MID) AF: 0.428 AC: 125 AN: 292

European-Non Finnish (NFE) AF: 0.387 AC: 26308 AN: 67954

Other (OTH) AF: 0.323 AC: 682 AN: 2112

Alfa AF: 0.226 Hom.: 594

Bravo AF: 0.300

Asia WGS AF: 0.332 AC: 1156 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	2.6
DANN	Benign	0.74
PhyloP100		-1.2
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: rs12495133; hg19: chr3-78921520;