3-78662200-T-C

Variant names:

• chr3-78662200-T-C
• rs9864412
• NM_002941.4:c.1967-86A>G

Variant summary

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

The NM_002941.4(ROBO1):​c.1967-86A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.467 in 1,266,680 control chromosomes in the GnomAD database, including 142,934 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 0.42 (13802 hom., cov: 26)
  • Exomes 𝑓: 0.47 (129132 hom.)
• Consequence: ROBO1 NM_002941.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.31
• Publications: 4 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=-0.9).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.491 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ROBO1	NM_002941.4	c.1967-86A>G		intron_variant	Intron 14 of 30	ENST00000464233.6	NP_002932.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ROBO1	ENST00000464233.6	c.1967-86A>G		intron_variant	Intron 14 of 30	5	NM_002941.4	ENSP00000420321.1

Frequencies

GnomAD3 genomes AF: 0.417 AC: 61402 AN: 147206 Hom.: 13816 Cov.: 26

Gnomad AFR AF: 0.240

Gnomad AMI AF: 0.565

Gnomad AMR AF: 0.486

Gnomad ASJ AF: 0.574

Gnomad EAS AF: 0.221

Gnomad SAS AF: 0.454

Gnomad FIN AF: 0.486

Gnomad MID AF: 0.577

Gnomad NFE AF: 0.495

Gnomad OTH AF: 0.444

GnomAD4 exome AF: 0.474 AC: 530181 AN: 1119380 Hom.: 129132 AF XY: 0.475 AC XY: 262577 AN XY: 553148

African (AFR) AF: 0.218 AC: 5378 AN: 24660

American (AMR) AF: 0.471 AC: 11052 AN: 23476

Ashkenazi Jewish (ASJ) AF: 0.573 AC: 10597 AN: 18500

East Asian (EAS) AF: 0.214 AC: 6958 AN: 32556

South Asian (SAS) AF: 0.460 AC: 26953 AN: 58654

European-Finnish (FIN) AF: 0.473 AC: 20452 AN: 43234

Middle Eastern (MID) AF: 0.512 AC: 2307 AN: 4502

European-Non Finnish (NFE) AF: 0.490 AC: 424864 AN: 866566

Other (OTH) AF: 0.458 AC: 21620 AN: 47232

GnomAD4 genome AF: 0.417 AC: 61389 AN: 147300 Hom.: 13802 Cov.: 26 AF XY: 0.420 AC XY: 30000 AN XY: 71492

African (AFR) AF: 0.240 AC: 9407 AN: 39252

American (AMR) AF: 0.486 AC: 7196 AN: 14816

Ashkenazi Jewish (ASJ) AF: 0.574 AC: 1985 AN: 3456

East Asian (EAS) AF: 0.221 AC: 1086 AN: 4924

South Asian (SAS) AF: 0.453 AC: 2112 AN: 4666

European-Finnish (FIN) AF: 0.486 AC: 4658 AN: 9588

Middle Eastern (MID) AF: 0.573 AC: 164 AN: 286

European-Non Finnish (NFE) AF: 0.495 AC: 33368 AN: 67356

Other (OTH) AF: 0.440 AC: 902 AN: 2052

Alfa AF: 0.437 Hom.: 2520

Bravo AF: 0.398

Asia WGS AF: 0.307 AC: 1071 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.0010
DANN	Benign	0.52
PhyloP100		-2.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs9864412; hg19: chr3-78711350; COSMIC: COSV71394473;