Genetic Variant ROBO4:c.1037-79G>A (chr11-124895272-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.1037-79G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.16 in 1,247,086 control chromosomes in the GnomAD database, including 16,735 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 0.16 ( 1999 hom., cov: 32)

Exomes 𝑓: 0.16 ( 14736 hom. )

Consequence

ROBO4
NM_019055.6 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0850

Publications

6 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:

Genome browser will be placed here

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=-0.8).

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.2 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
ROBO4	NM_019055.6 link	c.1037-79G>A	intron_variant	Intron 6 of 17	ENST00000306534.8	NP_061928.4	Q8WZ75-1
ROBO4	NM_001441183.1 link	c.1037-79G>A	intron_variant	Intron 6 of 17		NP_001428112.1
ROBO4	NM_001301088.2 link	c.602-79G>A	intron_variant	Intron 6 of 17		NP_001288017.1	Q8WZ75B4DYV8
LOC107984406	XR_001748429.3 link	n.334+3140C>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.1037-79G>A		intron_variant	Intron 6 of 17	1	NM_019055.6	ENSP00000304945.3		Q8WZ75-1

Frequencies

GnomAD3 genomes

AF:

0.159

AC:

24072

AN:

151854

Hom.:

1999

Cov.:

show subpopulations

Gnomad AFR

AF:

0.144

Gnomad AMI

AF:

0.221

Gnomad AMR

AF:

0.121

Gnomad ASJ

AF:

0.121

Gnomad EAS

AF:

0.133

Gnomad SAS

AF:

0.212

Gnomad FIN

AF:

0.287

Gnomad MID

AF:

0.161

Gnomad NFE

AF:

0.155

Gnomad OTH

AF:

0.146

GnomAD4 exome

AF:

0.160

AC:

175575

AN:

1095114

Hom.:

14736

Cov.:

AF XY:

0.162

AC XY:

90152

AN XY:

556906

show subpopulations

African (AFR)

AF:

0.143

AC:

3752

AN:

26204

American (AMR)

AF:

0.0882

AC:

3322

AN:

37684

Ashkenazi Jewish (ASJ)

AF:

0.123

AC:

2774

AN:

22502

East Asian (EAS)

AF:

0.161

AC:

5930

AN:

36850

South Asian (SAS)

AF:

0.207

AC:

15607

AN:

75316

European-Finnish (FIN)

AF:

0.266

AC:

13552

AN:

50978

Middle Eastern (MID)

AF:

0.168

AC:

635

AN:

3788

European-Non Finnish (NFE)

AF:

0.154

AC:

122570

AN:

793836

Other (OTH)

AF:

0.155

AC:

7433

AN:

47956

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

7936

15872

23807

31743

39679

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3878

7756

11634

15512

19390

<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:

0.158

AC:

24084

AN:

151972

Hom.:

1999

Cov.:

AF XY:

0.165

AC XY:

12262

AN XY:

74300

show subpopulations

African (AFR)

AF:

0.144

AC:

5988

AN:

41458

American (AMR)

AF:

0.121

AC:

1842

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.121

AC:

418

AN:

3464

East Asian (EAS)

AF:

0.133

AC:

683

AN:

5150

South Asian (SAS)

AF:

0.211

AC:

1013

AN:

4800

European-Finnish (FIN)

AF:

0.287

AC:

3037

AN:

10564

Middle Eastern (MID)

AF:

0.163

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.155

AC:

10546

AN:

67940

Other (OTH)

AF:

0.146

AC:

308

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1040

2079

3119

4158

5198

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

266

532

798

1064

1330

<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:

0.145

Hom.:

2821

Bravo

AF:

0.143

Asia WGS

AF:

0.188

AC:

652

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.80

CADD

Benign

8.6

(source)

DANN

Benign

0.90

PhyloP100

-0.085

Mutation Taster

=100/0

polymorphism (auto)

(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