Genetic Variant NM_019055.6:c.1864G>C (chr11-124891383-C-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PP5_ModerateBS2

The NM_019055.6(ROBO4):c.1864G>C(p.Asp622His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000697 in 1,564,888 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000075 ( 0 hom. )

Consequence

ROBO4
NM_019055.6 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 2.22

Publications

1 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: Likely_benign. The variant received -2 ACMG points.

PP5

Variant 11-124891383-C-G is Pathogenic according to our data. Variant chr11-124891383-C-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 560401.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High AC in GnomAdExome4 at 106 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ROBO4	NM_019055.6 link	c.1864G>C	p.Asp622His	missense_variant	Exon 12 of 18	ENST00000306534.8	NP_061928.4	Q8WZ75-1
ROBO4	NM_001441183.1 link	c.1864G>C	p.Asp622His	missense_variant	Exon 12 of 18		NP_001428112.1
ROBO4	NM_001301088.2 link	c.1429G>C	p.Asp477His	missense_variant	Exon 12 of 18		NP_001288017.1	Q8WZ75B4DYV8
ROBO4	XM_011542875.2 link	c.538G>C	p.Asp180His	missense_variant	Exon 5 of 11		XP_011541177.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ROBO4	ENST00000306534.8 link	c.1864G>C	p.Asp622His	missense_variant	Exon 12 of 18	1	NM_019055.6	ENSP00000304945.3		Q8WZ75-1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152196

Hom.:

Cov.:

show subpopulations

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:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000518

AC:

AN:

212208

AF XY:

0.0000534

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000113

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000750

AC:

106

AN:

1412692

Hom.:

Cov.:

AF XY:

0.0000789

AC XY:

AN XY:

696722

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32264

American (AMR)

AF:

0.00

AC:

AN:

40044

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22404

East Asian (EAS)

AF:

0.00

AC:

AN:

39312

South Asian (SAS)

AF:

0.00

AC:

AN:

76906

European-Finnish (FIN)

AF:

0.0000585

AC:

AN:

51292

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5236

European-Non Finnish (NFE)

AF:

0.0000911

AC:

AN:

1087038

Other (OTH)

AF:

0.0000687

AC:

AN:

58196

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

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

AF:

0.0000197

AC:

AN:

152196

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74348

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41444

American (AMR)

AF:

0.00

AC:

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68040

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000189

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Bicuspid aortic valve;C0856747:Ascending tubular aorta aneurysm

Pathogenic:1

Baylor-Hopkins Center for Mendelian Genomics, Johns Hopkins University School of Medicine

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.28

BayesDel_addAF

Benign

-0.10

BayesDel_noAF

Benign

-0.17

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.14

T;T

Eigen

Pathogenic

0.70

Eigen_PC

Pathogenic

0.69

FATHMM_MKL

Benign

0.71

LIST_S2

Benign

0.82

T;T

M_CAP

Benign

0.036

MetaRNN

Uncertain

0.53

D;D

MetaSVM

Uncertain

-0.22

MutationAssessor

Uncertain

2.6

M;.

PhyloP100

2.2

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-1.5

N;N

REVEL

Benign

0.17

Sift

Uncertain

0.011

D;D

Sift4G

Uncertain

0.0070

D;D

Polyphen

1.0

D;.

Vest4

0.52

MVP

0.85

MPC

0.48

ClinPred

0.42

GERP RS

5.9

Varity_R

0.20

gMVP

0.57

Mutation Taster

=10/90

disease causing (ClinVar)

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over