Genetic Variant ROBO4:p.Asp622Tyr (chr11-124891383-C-A) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PM5

The NM_019055.6(ROBO4):c.1864G>T(p.Asp622Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D622H) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

ROBO4
NM_019055.6 missense

Scores

Clinical Significance

Not reported in ClinVar

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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ROBO4	NM_019055.6 link	c.1864G>T	p.Asp622Tyr	missense_variant	Exon 12 of 18	ENST00000306534.8	NP_061928.4	Q8WZ75-1
ROBO4	NM_001441183.1 link	c.1864G>T	p.Asp622Tyr	missense_variant	Exon 12 of 18		NP_001428112.1
ROBO4	NM_001301088.2 link	c.1429G>T	p.Asp477Tyr	missense_variant	Exon 12 of 18		NP_001288017.1	Q8WZ75B4DYV8
ROBO4	XM_011542875.2 link	c.538G>T	p.Asp180Tyr	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>T	p.Asp622Tyr	missense_variant	Exon 12 of 18	1	NM_019055.6	ENSP00000304945.3		Q8WZ75-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000471

AC:

AN:

212208

AF XY:

0.00

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:

0.0000103

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1412692

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

696722

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:

0.00

AC:

AN:

51292

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5236

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1087038

Other (OTH)

AF:

0.00

AC:

AN:

58196

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000165

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.26

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Uncertain

-0.040

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.19

T;T

Eigen

Pathogenic

0.71

Eigen_PC

Pathogenic

0.69

FATHMM_MKL

Benign

0.63

LIST_S2

Benign

0.83

T;T

M_CAP

Benign

0.054

MetaRNN

Uncertain

0.63

D;D

MetaSVM

Uncertain

-0.20

MutationAssessor

Uncertain

2.6

M;.

PhyloP100

2.2

PrimateAI

Uncertain

0.53

PROVEAN

Benign

-2.2

N;N

REVEL

Benign

0.20

Sift

Uncertain

0.0050

D;D

Sift4G

Uncertain

0.0040

D;D

Polyphen

1.0

D;.

Vest4

0.68

MutPred

0.22

Gain of MoRF binding (P = 0.0344);.;

MVP

0.85

MPC

0.49

ClinPred

0.83

GERP RS

5.9

Varity_R

0.30

gMVP

0.61

Mutation Taster

=51/49

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over