rs2255164

Variant names:

• chr3-78668358-G-A
• rs2255164
• NM_002941.4:c.1631-56C>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.1631-56C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.489 in 1,597,854 control chromosomes in the GnomAD database, including 194,176 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 0.46 (16749 hom., cov: 32)
  • Exomes 𝑓: 0.49 (177427 hom.)
• Consequence: ROBO1 NM_002941.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.299
• 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: PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics
• pituitary hormone deficiency, combined or isolated, 8

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

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• congenital heart disease

  Inheritance: AR, AD Classification: LIMITED Submitted by: ClinGen
• nystagmus, congenital, autosomal recessive

  Inheritance: AR Classification: LIMITED Submitted by: PanelApp Australia

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.509 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ROBO1	NM_002941.4	MANE Select	c.1631-56C>T		intron	N/A	NP_002932.1	Q9Y6N7-1
	ROBO1	NM_133631.4		c.1523-56C>T		intron	N/A	NP_598334.2	Q9Y6N7-5
	ROBO1	NM_001145845.2		c.1523-56C>T		intron	N/A	NP_001139317.1	Q9Y6N7-6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ROBO1	ENST00000464233.6	TSL:5 MANE Select	c.1631-56C>T		intron	N/A	ENSP00000420321.1	Q9Y6N7-1
	ROBO1	ENST00000495273.5	TSL:1	c.1523-56C>T		intron	N/A	ENSP00000420637.1	Q9Y6N7-5
	ROBO1	ENST00000467549.5	TSL:1	c.1523-56C>T		intron	N/A	ENSP00000417992.1	Q9Y6N7-6

Frequencies

GnomAD3 genomes AF: 0.462 AC: 70193 AN: 151842 Hom.: 16759 Cov.: 32

Gnomad AFR AF: 0.372

Gnomad AMI AF: 0.596

Gnomad AMR AF: 0.508

Gnomad ASJ AF: 0.596

Gnomad EAS AF: 0.219

Gnomad SAS AF: 0.456

Gnomad FIN AF: 0.478

Gnomad MID AF: 0.583

Gnomad NFE AF: 0.514

Gnomad OTH AF: 0.485

GnomAD4 exome AF: 0.492 AC: 711080 AN: 1445894 Hom.: 177427 Cov.: 28 AF XY: 0.492 AC XY: 353766 AN XY: 718570

African (AFR) AF: 0.361 AC: 11872 AN: 32928

American (AMR) AF: 0.488 AC: 21396 AN: 43806

Ashkenazi Jewish (ASJ) AF: 0.589 AC: 15068 AN: 25604

East Asian (EAS) AF: 0.215 AC: 8480 AN: 39470

South Asian (SAS) AF: 0.465 AC: 39781 AN: 85586

European-Finnish (FIN) AF: 0.482 AC: 25616 AN: 53160

Middle Eastern (MID) AF: 0.539 AC: 3060 AN: 5682

European-Non Finnish (NFE) AF: 0.506 AC: 556968 AN: 1100020

Other (OTH) AF: 0.484 AC: 28839 AN: 59638

GnomAD4 genome AF: 0.462 AC: 70198 AN: 151960 Hom.: 16749 Cov.: 32 AF XY: 0.463 AC XY: 34350 AN XY: 74270

African (AFR) AF: 0.371 AC: 15381 AN: 41426

American (AMR) AF: 0.508 AC: 7748 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.596 AC: 2068 AN: 3468

East Asian (EAS) AF: 0.218 AC: 1128 AN: 5166

South Asian (SAS) AF: 0.455 AC: 2195 AN: 4826

European-Finnish (FIN) AF: 0.478 AC: 5048 AN: 10550

Middle Eastern (MID) AF: 0.579 AC: 169 AN: 292

European-Non Finnish (NFE) AF: 0.514 AC: 34902 AN: 67952

Other (OTH) AF: 0.480 AC: 1015 AN: 2114

Alfa AF: 0.499 Hom.: 23861

Bravo AF: 0.455

Asia WGS AF: 0.314 AC: 1095 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	4.4
DANN	Benign	0.39
PhyloP100		0.30
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: rs2255164; hg19: chr3-78717508; COSMIC: COSV71394474;