Genetic Variant ROBO4:c.71-133G>A (chr11-124897394-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_019055.6(ROBO4):c.71-133G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0427 in 717,918 control chromosomes in the GnomAD database, including 884 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 0.035 ( 165 hom., cov: 32)

Exomes 𝑓: 0.045 ( 719 hom. )

Consequence

ROBO4
NM_019055.6 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.635

Publications

4 publications found

Variant links:

Genes affected

ROBO4 (HGNC:17985): (roundabout guidance receptor 4) Predicted to enable cell-cell adhesion mediator activity. Involved in angiogenesis and establishment of endothelial barrier. Located in extracellular exosome. Implicated in aortic valve disease 3. [provided by Alliance of Genome Resources, Apr 2022]

ROBO4 Gene-Disease associations (from GenCC):

aortic valve disease 3
Inheritance: AD Classification: STRONG, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), PanelApp Australia

ROBO4 links:

ENSG00000254943 (HGNC:):

ENSG00000254943 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.82).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0544 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
ROBO4	NM_019055.6 link	c.71-133G>A	intron_variant	Intron 1 of 17	ENST00000306534.8	NP_061928.4	Q8WZ75-1
ROBO4	NM_001441183.1 link	c.71-133G>A	intron_variant	Intron 1 of 17		NP_001428112.1
ROBO4	NM_001301088.2 link	c.-160+332G>A	intron_variant	Intron 1 of 17		NP_001288017.1	Q8WZ75B4DYV8
LOC107984406	XR_001748429.3 link	n.334+5262C>T	intron_variant	Intron 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ROBO4	ENST00000306534.8 link	c.71-133G>A		intron_variant	Intron 1 of 17	1	NM_019055.6	ENSP00000304945.3		Q8WZ75-1

Frequencies

GnomAD3 genomes

AF:

0.0350

AC:

5328

AN:

152150

Hom.:

165

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00973

Gnomad AMI

AF:

0.0121

Gnomad AMR

AF:

0.0238

Gnomad ASJ

AF:

0.0153

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00662

Gnomad FIN

AF:

0.0567

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0558

Gnomad OTH

AF:

0.0320

GnomAD4 exome

AF:

0.0448

AC:

25348

AN:

565650

Hom.:

719

AF XY:

0.0436

AC XY:

12530

AN XY:

287488

show subpopulations

African (AFR)

AF:

0.00867

AC:

127

AN:

14652

American (AMR)

AF:

0.0236

AC:

382

AN:

16184

Ashkenazi Jewish (ASJ)

AF:

0.0188

AC:

264

AN:

14054

East Asian (EAS)

AF:

0.0000994

AC:

AN:

30192

South Asian (SAS)

AF:

0.00589

AC:

223

AN:

37892

European-Finnish (FIN)

AF:

0.0572

AC:

1647

AN:

28806

Middle Eastern (MID)

AF:

0.00182

AC:

AN:

3850

European-Non Finnish (NFE)

AF:

0.0553

AC:

21581

AN:

390454

Other (OTH)

AF:

0.0377

AC:

1114

AN:

29566

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

1284

2567

3851

5134

6418

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

460

920

1380

1840

2300

<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

AF:

0.0350

AC:

5329

AN:

152268

Hom.:

165

Cov.:

AF XY:

0.0330

AC XY:

2456

AN XY:

74458

show subpopulations

African (AFR)

AF:

0.00970

AC:

403

AN:

41560

American (AMR)

AF:

0.0237

AC:

363

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.0153

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5178

South Asian (SAS)

AF:

0.00684

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.0567

AC:

601

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0558

AC:

3797

AN:

68002

Other (OTH)

AF:

0.0317

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

256

511

767

1022

1278

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

124

186

248

310

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0510

Hom.:

333

Bravo

AF:

0.0324

Asia WGS

AF:

0.00289

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

5.9

(source)

DANN

Benign

0.32

PhyloP100

0.64

PromoterAI

0.030

Neutral

(source)

Mutation Taster

=100/0

polymorphism

(source)

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over