3-78614806-G-A

Variant names:

• chr3-78614806-G-A
• rs1027832
• NM_002941.4:c.4283-6C>T

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.4283-6C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.406 in 1,543,268 control chromosomes in the GnomAD database, including 129,111 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 0.37 (11037 hom., cov: 29)
  • Exomes 𝑓: 0.41 (118074 hom.)
• Consequence: ROBO1 NM_002941.4 splice_region, intron
• Scores: Splicing: ADA: 0.00003322
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.360
• Publications: 13 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 3-78614806-G-A is Benign according to our data. Variant chr3-78614806-G-A is described in ClinVar as Benign. ClinVar VariationId is 1642377.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.491 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.4283-6C>T		splice_region intron	N/A	NP_002932.1	Q9Y6N7-1
	ROBO1	NM_133631.4		c.4148-6C>T		splice_region intron	N/A	NP_598334.2	Q9Y6N7-5
	ROBO1	NM_001145845.2		c.3983-6C>T		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.4283-6C>T		splice_region intron	N/A	ENSP00000420321.1	Q9Y6N7-1
	ROBO1	ENST00000495273.5	TSL:1	c.4148-6C>T		splice_region intron	N/A	ENSP00000420637.1	Q9Y6N7-5
	ROBO1	ENST00000467549.5	TSL:1	c.3983-6C>T		splice_region intron	N/A	ENSP00000417992.1	Q9Y6N7-6

Frequencies

GnomAD3 genomes AF: 0.373 AC: 54878 AN: 147056 Hom.: 11036 Cov.: 29

Gnomad AFR AF: 0.212

Gnomad AMI AF: 0.549

Gnomad AMR AF: 0.500

Gnomad ASJ AF: 0.445

Gnomad EAS AF: 0.326

Gnomad SAS AF: 0.434

Gnomad FIN AF: 0.487

Gnomad MID AF: 0.424

Gnomad NFE AF: 0.416

Gnomad OTH AF: 0.400

GnomAD2 exomes AF: 0.454 AC: 80681 AN: 177654 AF XY: 0.453

Gnomad AFR exome AF: 0.244

Gnomad AMR exome AF: 0.596

Gnomad ASJ exome AF: 0.470

Gnomad EAS exome AF: 0.360

Gnomad FIN exome AF: 0.493

Gnomad NFE exome AF: 0.441

Gnomad OTH exome AF: 0.450

GnomAD4 exome AF: 0.410 AC: 571734 AN: 1396124 Hom.: 118074 Cov.: 34 AF XY: 0.411 AC XY: 284078 AN XY: 691988

African (AFR) AF: 0.205 AC: 6275 AN: 30636

American (AMR) AF: 0.562 AC: 20003 AN: 35584

Ashkenazi Jewish (ASJ) AF: 0.451 AC: 11016 AN: 24424

East Asian (EAS) AF: 0.291 AC: 10974 AN: 37694

South Asian (SAS) AF: 0.432 AC: 33017 AN: 76468

European-Finnish (FIN) AF: 0.465 AC: 22089 AN: 47486

Middle Eastern (MID) AF: 0.413 AC: 2272 AN: 5496

European-Non Finnish (NFE) AF: 0.410 AC: 442732 AN: 1080834

Other (OTH) AF: 0.406 AC: 23356 AN: 57502

GnomAD4 genome AF: 0.373 AC: 54888 AN: 147144 Hom.: 11037 Cov.: 29 AF XY: 0.380 AC XY: 27149 AN XY: 71536

African (AFR) AF: 0.212 AC: 8338 AN: 39408

American (AMR) AF: 0.501 AC: 7492 AN: 14964

Ashkenazi Jewish (ASJ) AF: 0.445 AC: 1525 AN: 3426

East Asian (EAS) AF: 0.325 AC: 1623 AN: 4996

South Asian (SAS) AF: 0.434 AC: 2028 AN: 4672

European-Finnish (FIN) AF: 0.487 AC: 4606 AN: 9452

Middle Eastern (MID) AF: 0.418 AC: 118 AN: 282

European-Non Finnish (NFE) AF: 0.416 AC: 27844 AN: 66990

Other (OTH) AF: 0.399 AC: 821 AN: 2056

Alfa AF: 0.400 Hom.: 52695

Bravo AF: 0.361

Asia WGS AF: 0.366 AC: 1260 AN: 3442

ClinVar

ClinVar submissions as Germline

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	-0.84
CADD	Benign	1.2
DANN	Benign	0.44
PhyloP100		-0.36
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000033
dbscSNV1_RF	Benign	0.012
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: rs1027832; hg19: chr3-78663956; COSMIC: COSV107525297;