Genetic Variant NM_019055.6:c.283G>T (chr11-124897049-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 4P and 4B. PM2PM5BP4_Strong

The NM_019055.6(ROBO4):c.283G>T(p.Ala95Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,330 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. 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. A95T) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

ROBO4
NM_019055.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.687

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: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr11-124897049-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 560395.Status of the report is criteria_provided_single_submitter, 1 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.033569217).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ROBO4	NM_019055.6 link	c.283G>T	p.Ala95Ser	missense_variant	Exon 2 of 18	ENST00000306534.8	NP_061928.4	Q8WZ75-1
ROBO4	NM_001441183.1 link	c.283G>T	p.Ala95Ser	missense_variant	Exon 2 of 18		NP_001428112.1
ROBO4	NM_001301088.2 link	c.-153G>T		5_prime_UTR_variant	Exon 2 of 18		NP_001288017.1	Q8WZ75B4DYV8
LOC107984406	XR_001748429.3 link	n.334+4917C>A		intron_variant	Intron 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ROBO4	ENST00000306534.8 link	c.283G>T	p.Ala95Ser	missense_variant	Exon 2 of 18	1	NM_019055.6	ENSP00000304945.3		Q8WZ75-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

249776

AF XY:

0.00

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461330

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726938

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33474

American (AMR)

AF:

0.00

AC:

AN:

44652

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26084

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39692

South Asian (SAS)

AF:

0.00

AC:

AN:

86166

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53360

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5754

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111790

Other (OTH)

AF:

0.00

AC:

AN:

60358

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

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

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.59

CADD

Benign

1.3

(source)

DANN

Benign

0.89

DEOGEN2

Benign

0.060

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.088

LIST_S2

Benign

0.57

M_CAP

Benign

0.019

MetaRNN

Benign

0.034

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.065

PhyloP100

-0.69

PrimateAI

Benign

0.23

PROVEAN

Benign

0.15

REVEL

Benign

0.021

Sift

Benign

0.44

Sift4G

Benign

0.26

Polyphen

0.045

Vest4

0.13

MutPred

0.32

Gain of glycosylation at A95 (P = 0.0288);

MVP

0.23

MPC

0.087

ClinPred

0.015

GERP RS

-2.7

Varity_R

0.054

gMVP

0.18

Mutation Taster

=98/2

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over