rs7636043

Variant names:

• chr3-78627317-A-G
• rs7636043
• NM_002941.4:c.3875+4T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002941.4(ROBO1):​c.3875+4T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.966 in 1,611,048 control chromosomes in the GnomAD database, including 751,405 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.97 (71634 hom., cov: 32)
  • Exomes 𝑓: 0.97 (679771 hom.)
• Consequence: ROBO1 NM_002941.4 splice_region, intron
• Scores: Splicing: ADA: 0.00001445
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.02
• Publications: 10 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 3-78627317-A-G is Benign according to our data. Variant chr3-78627317-A-G is described in ClinVar as Benign. ClinVar VariationId is 1542355.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.97 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+4T>C		splice_region intron	N/A	NP_002932.1	Q9Y6N7-1
	ROBO1	NM_133631.4		c.3740+4T>C		splice_region intron	N/A	NP_598334.2	Q9Y6N7-5
	ROBO1	NM_001145845.2		c.3575+4T>C		splice_region 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.3875+4T>C		splice_region intron	N/A	ENSP00000420321.1	Q9Y6N7-1
	ROBO1	ENST00000495273.5	TSL:1	c.3740+4T>C		splice_region intron	N/A	ENSP00000420637.1	Q9Y6N7-5
	ROBO1	ENST00000467549.5	TSL:1	c.3575+4T>C		splice_region intron	N/A	ENSP00000417992.1	Q9Y6N7-6

Frequencies

GnomAD3 genomes AF: 0.970 AC: 147570 AN: 152164 Hom.: 71577 Cov.: 32

Gnomad AFR AF: 0.978

Gnomad AMI AF: 0.992

Gnomad AMR AF: 0.976

Gnomad ASJ AF: 0.982

Gnomad EAS AF: 0.991

Gnomad SAS AF: 0.925

Gnomad FIN AF: 0.966

Gnomad MID AF: 0.965

Gnomad NFE AF: 0.964

Gnomad OTH AF: 0.976

GnomAD2 exomes AF: 0.966 AC: 236571 AN: 244810 AF XY: 0.964

Gnomad AFR exome AF: 0.979

Gnomad AMR exome AF: 0.984

Gnomad ASJ exome AF: 0.982

Gnomad EAS exome AF: 0.992

Gnomad FIN exome AF: 0.964

Gnomad NFE exome AF: 0.964

Gnomad OTH exome AF: 0.967

GnomAD4 exome AF: 0.965 AC: 1408085 AN: 1458766 Hom.: 679771 Cov.: 44 AF XY: 0.964 AC XY: 699262 AN XY: 725310

African (AFR) AF: 0.981 AC: 32820 AN: 33448

American (AMR) AF: 0.984 AC: 43725 AN: 44438

Ashkenazi Jewish (ASJ) AF: 0.982 AC: 25544 AN: 26016

East Asian (EAS) AF: 0.996 AC: 39345 AN: 39522

South Asian (SAS) AF: 0.931 AC: 79832 AN: 85726

European-Finnish (FIN) AF: 0.964 AC: 51377 AN: 53298

Middle Eastern (MID) AF: 0.953 AC: 5485 AN: 5756

European-Non Finnish (NFE) AF: 0.965 AC: 1071711 AN: 1110324

Other (OTH) AF: 0.967 AC: 58246 AN: 60238

GnomAD4 genome AF: 0.970 AC: 147686 AN: 152282 Hom.: 71634 Cov.: 32 AF XY: 0.970 AC XY: 72187 AN XY: 74454

African (AFR) AF: 0.978 AC: 40665 AN: 41564

American (AMR) AF: 0.976 AC: 14926 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.982 AC: 3408 AN: 3472

East Asian (EAS) AF: 0.991 AC: 5118 AN: 5162

South Asian (SAS) AF: 0.925 AC: 4464 AN: 4824

European-Finnish (FIN) AF: 0.966 AC: 10257 AN: 10622

Middle Eastern (MID) AF: 0.966 AC: 284 AN: 294

European-Non Finnish (NFE) AF: 0.964 AC: 65596 AN: 68024

Other (OTH) AF: 0.975 AC: 2063 AN: 2116

Alfa AF: 0.968 Hom.: 50572

Bravo AF: 0.973

Asia WGS AF: 0.956 AC: 3325 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.0010
DANN	Benign	0.46
PhyloP100		-2.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000014
dbscSNV1_RF	Benign	0.0
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: rs7636043; hg19: chr3-78676467;