NM_002941.4:c.3875+49C>T

Variant names:

• chr3-78627272-G-A
• rs7614084
• NM_002941.4:c.3875+49C>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.3875+49C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.399 in 1,576,350 control chromosomes in the GnomAD database, including 127,485 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 (10984 hom., cov: 33)
  • Exomes 𝑓: 0.40 (116501 hom.)
• Consequence: ROBO1 NM_002941.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.329
• 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: Labcorp Genetics (formerly Invitae), Ambry Genetics
• pituitary hormone deficiency, combined or isolated, 8

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

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

  Inheritance: AR, AD Classification: LIMITED Submitted by: ClinGen

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 = 0.447 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.3875+49C>T		intron	N/A	NP_002932.1
	ROBO1	NM_133631.4		c.3740+49C>T		intron	N/A	NP_598334.2
	ROBO1	NM_001145845.2		c.3575+49C>T		intron	N/A	NP_001139317.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ROBO1	ENST00000464233.6	TSL:5 MANE Select	c.3875+49C>T		intron	N/A	ENSP00000420321.1
	ROBO1	ENST00000495273.5	TSL:1	c.3740+49C>T		intron	N/A	ENSP00000420637.1
	ROBO1	ENST00000467549.5	TSL:1	c.3575+49C>T		intron	N/A	ENSP00000417992.1

Frequencies

GnomAD3 genomes AF: 0.373 AC: 56627 AN: 151936 Hom.: 10987 Cov.: 33

Gnomad AFR AF: 0.271

Gnomad AMI AF: 0.523

Gnomad AMR AF: 0.455

Gnomad ASJ AF: 0.447

Gnomad EAS AF: 0.265

Gnomad SAS AF: 0.389

Gnomad FIN AF: 0.411

Gnomad MID AF: 0.472

Gnomad NFE AF: 0.410

Gnomad OTH AF: 0.408

GnomAD2 exomes AF: 0.394 AC: 84184 AN: 213820 AF XY: 0.391

Gnomad AFR exome AF: 0.263

Gnomad AMR exome AF: 0.472

Gnomad ASJ exome AF: 0.451

Gnomad EAS exome AF: 0.261

Gnomad FIN exome AF: 0.414

Gnomad NFE exome AF: 0.404

Gnomad OTH exome AF: 0.406

GnomAD4 exome AF: 0.402 AC: 572014 AN: 1424296 Hom.: 116501 Cov.: 28 AF XY: 0.401 AC XY: 282608 AN XY: 704410

African (AFR) AF: 0.264 AC: 8659 AN: 32810

American (AMR) AF: 0.470 AC: 19130 AN: 40738

Ashkenazi Jewish (ASJ) AF: 0.450 AC: 11081 AN: 24606

East Asian (EAS) AF: 0.238 AC: 9245 AN: 38876

South Asian (SAS) AF: 0.385 AC: 31298 AN: 81360

European-Finnish (FIN) AF: 0.409 AC: 21288 AN: 52014

Middle Eastern (MID) AF: 0.421 AC: 2366 AN: 5624

European-Non Finnish (NFE) AF: 0.409 AC: 445582 AN: 1089468

Other (OTH) AF: 0.397 AC: 23365 AN: 58800

GnomAD4 genome AF: 0.372 AC: 56638 AN: 152054 Hom.: 10984 Cov.: 33 AF XY: 0.375 AC XY: 27885 AN XY: 74306

African (AFR) AF: 0.270 AC: 11223 AN: 41496

American (AMR) AF: 0.456 AC: 6960 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.447 AC: 1550 AN: 3470

East Asian (EAS) AF: 0.264 AC: 1361 AN: 5156

South Asian (SAS) AF: 0.388 AC: 1867 AN: 4808

European-Finnish (FIN) AF: 0.411 AC: 4347 AN: 10586

Middle Eastern (MID) AF: 0.463 AC: 136 AN: 294

European-Non Finnish (NFE) AF: 0.410 AC: 27861 AN: 67950

Other (OTH) AF: 0.405 AC: 856 AN: 2112

Alfa AF: 0.399 Hom.: 31663

Bravo AF: 0.370

Asia WGS AF: 0.317 AC: 1105 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	1.7
DANN	Benign	0.66
PhyloP100		0.33
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: rs7614084; hg19: chr3-78676422; COSMIC: COSV71394443; COSMIC: COSV71394443;