NM_002941.4:c.500-28G>T

Variant names:

• chr3-78746928-C-A
• rs2304503
• NM_002941.4:c.500-28G>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.500-28G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.506 in 1,454,514 control chromosomes in the GnomAD database, including 189,620 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 0.47 (17905 hom., cov: 32)
  • Exomes 𝑓: 0.51 (171715 hom.)
• Consequence: ROBO1 NM_002941.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.05
• Publications: 12 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 (AMR) allele frequency at 95% confidence interval = 0.542 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ROBO1	NM_002941.4	c.500-28G>T		intron_variant	Intron 4 of 30	ENST00000464233.6	NP_002932.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ROBO1	ENST00000464233.6	c.500-28G>T		intron_variant	Intron 4 of 30	5	NM_002941.4	ENSP00000420321.1

Frequencies

GnomAD3 genomes AF: 0.473 AC: 71841 AN: 151832 Hom.: 17909 Cov.: 32

Gnomad AFR AF: 0.344

Gnomad AMI AF: 0.578

Gnomad AMR AF: 0.552

Gnomad ASJ AF: 0.590

Gnomad EAS AF: 0.238

Gnomad SAS AF: 0.541

Gnomad FIN AF: 0.505

Gnomad MID AF: 0.592

Gnomad NFE AF: 0.533

Gnomad OTH AF: 0.503

GnomAD2 exomes AF: 0.503 AC: 96289 AN: 191400 AF XY: 0.506

Gnomad AFR exome AF: 0.348

Gnomad AMR exome AF: 0.583

Gnomad ASJ exome AF: 0.593

Gnomad EAS exome AF: 0.227

Gnomad FIN exome AF: 0.518

Gnomad NFE exome AF: 0.531

Gnomad OTH exome AF: 0.535

GnomAD4 exome AF: 0.510 AC: 664013 AN: 1302564 Hom.: 171715 Cov.: 25 AF XY: 0.512 AC XY: 326505 AN XY: 638064

African (AFR) AF: 0.348 AC: 10469 AN: 30098

American (AMR) AF: 0.569 AC: 18045 AN: 31720

Ashkenazi Jewish (ASJ) AF: 0.584 AC: 12037 AN: 20606

East Asian (EAS) AF: 0.238 AC: 8738 AN: 36660

South Asian (SAS) AF: 0.532 AC: 32681 AN: 61426

European-Finnish (FIN) AF: 0.515 AC: 24327 AN: 47274

Middle Eastern (MID) AF: 0.568 AC: 2902 AN: 5110

European-Non Finnish (NFE) AF: 0.520 AC: 528650 AN: 1017096

Other (OTH) AF: 0.498 AC: 26164 AN: 52574

GnomAD4 genome AF: 0.473 AC: 71845 AN: 151950 Hom.: 17905 Cov.: 32 AF XY: 0.476 AC XY: 35314 AN XY: 74250

African (AFR) AF: 0.343 AC: 14225 AN: 41432

American (AMR) AF: 0.552 AC: 8420 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.590 AC: 2045 AN: 3468

East Asian (EAS) AF: 0.238 AC: 1234 AN: 5176

South Asian (SAS) AF: 0.540 AC: 2603 AN: 4816

European-Finnish (FIN) AF: 0.505 AC: 5332 AN: 10548

Middle Eastern (MID) AF: 0.575 AC: 169 AN: 294

European-Non Finnish (NFE) AF: 0.533 AC: 36242 AN: 67946

Other (OTH) AF: 0.498 AC: 1048 AN: 2106

Alfa AF: 0.518 Hom.: 34625

Bravo AF: 0.465

Asia WGS AF: 0.368 AC: 1282 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	7.7
DANN	Benign	0.54
PhyloP100		-1.0
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: rs2304503; hg19: chr3-78796078; COSMIC: COSV71397238;