dbSNP rs9864412: ROBO1:c.1967-86A>T (chr3-78662200-T-A) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_002941.4(ROBO1):c.1967-86A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000232 in 1,122,140 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.0 ( 0 hom., cov: 26)

Exomes 𝑓: 0.000023 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

ROBO1
NM_002941.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.31

Publications

4 publications found

Variant links:

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

ROBO1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.87).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ROBO1	NM_002941.4 link	c.1967-86A>T		intron_variant	Intron 14 of 30	ENST00000464233.6	NP_002932.1	Q9Y6N7-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ROBO1	ENST00000464233.6 link	c.1967-86A>T		intron_variant	Intron 14 of 30	5	NM_002941.4	ENSP00000420321.1		Q9Y6N7-1

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

147376

Hom.:

Cov.:

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000232

AC:

AN:

1122140

Hom.:

AF XY:

0.0000252

AC XY:

AN XY:

554552

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

24714

American (AMR)

AF:

0.0000425

AC:

AN:

23534

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18552

East Asian (EAS)

AF:

0.00

AC:

AN:

32600

South Asian (SAS)

AF:

0.0000680

AC:

AN:

58796

European-Finnish (FIN)

AF:

0.0000461

AC:

AN:

43350

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4520

European-Non Finnish (NFE)

AF:

0.0000207

AC:

AN:

868732

Other (OTH)

AF:

0.0000211

AC:

AN:

47342

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.267

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

147376

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

71476

African (AFR)

AF:

0.00

AC:

AN:

39190

American (AMR)

AF:

0.00

AC:

AN:

14814

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3458

East Asian (EAS)

AF:

0.00

AC:

AN:

4944

South Asian (SAS)

AF:

0.00

AC:

AN:

4688

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

310

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67422

Other (OTH)

AF:

0.00

AC:

AN:

2034

Alfa

AF:

0.00

Hom.:

2520

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

0.0010

(source)

DANN

Benign

0.71

PhyloP100

-2.3

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over