chr3-78631428-T-C

Variant names:

• chr3-78631428-T-C
• rs6548592
• NM_002941.4:c.3482-123A>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.3482-123A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.492 in 1,055,962 control chromosomes in the GnomAD database, including 130,613 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 0.51 (19965 hom., cov: 32)
  • Exomes 𝑓: 0.49 (110648 hom.)
• Consequence: ROBO1 NM_002941.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.50
• 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: 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=-0.82).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.537 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.3482-123A>G		intron	N/A	NP_002932.1	Q9Y6N7-1
	ROBO1	NM_133631.4		c.3347-123A>G		intron	N/A	NP_598334.2	Q9Y6N7-5
	ROBO1	NM_001145845.2		c.3182-123A>G		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.3482-123A>G		intron	N/A	ENSP00000420321.1	Q9Y6N7-1
	ROBO1	ENST00000495273.5	TSL:1	c.3347-123A>G		intron	N/A	ENSP00000420637.1	Q9Y6N7-5
	ROBO1	ENST00000467549.5	TSL:1	c.3182-123A>G		intron	N/A	ENSP00000417992.1	Q9Y6N7-6

Frequencies

GnomAD3 genomes AF: 0.508 AC: 77222 AN: 151922 Hom.: 19959 Cov.: 32

Gnomad AFR AF: 0.537

Gnomad AMI AF: 0.611

Gnomad AMR AF: 0.546

Gnomad ASJ AF: 0.529

Gnomad EAS AF: 0.300

Gnomad SAS AF: 0.470

Gnomad FIN AF: 0.452

Gnomad MID AF: 0.576

Gnomad NFE AF: 0.506

Gnomad OTH AF: 0.525

GnomAD4 exome AF: 0.489 AC: 441959 AN: 903920 Hom.: 110648 AF XY: 0.489 AC XY: 218900 AN XY: 447782

African (AFR) AF: 0.535 AC: 11253 AN: 21032

American (AMR) AF: 0.542 AC: 10131 AN: 18700

Ashkenazi Jewish (ASJ) AF: 0.522 AC: 8265 AN: 15824

East Asian (EAS) AF: 0.263 AC: 8581 AN: 32676

South Asian (SAS) AF: 0.460 AC: 19857 AN: 43192

European-Finnish (FIN) AF: 0.462 AC: 18180 AN: 39326

Middle Eastern (MID) AF: 0.515 AC: 1728 AN: 3354

European-Non Finnish (NFE) AF: 0.499 AC: 344127 AN: 689668

Other (OTH) AF: 0.494 AC: 19837 AN: 40148

GnomAD4 genome AF: 0.508 AC: 77255 AN: 152042 Hom.: 19965 Cov.: 32 AF XY: 0.506 AC XY: 37625 AN XY: 74304

African (AFR) AF: 0.537 AC: 22268 AN: 41462

American (AMR) AF: 0.546 AC: 8345 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.529 AC: 1835 AN: 3470

East Asian (EAS) AF: 0.300 AC: 1553 AN: 5180

South Asian (SAS) AF: 0.469 AC: 2261 AN: 4824

European-Finnish (FIN) AF: 0.452 AC: 4767 AN: 10538

Middle Eastern (MID) AF: 0.571 AC: 168 AN: 294

European-Non Finnish (NFE) AF: 0.506 AC: 34404 AN: 67980

Other (OTH) AF: 0.520 AC: 1098 AN: 2110

Alfa AF: 0.509 Hom.: 5095

Bravo AF: 0.512

Asia WGS AF: 0.399 AC: 1390 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.20
DANN	Benign	0.77
PhyloP100		-1.5
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: rs6548592; hg19: chr3-78680578; COSMIC: COSV71397154;