Variant 11-124885119-C-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_019055.6(ROBO4):c.2923G>C(p.Gly975Arg) 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 1,461,822 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

ROBO4
NM_019055.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.11

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 links:

ROBO4 (HGNC:):

ROBO4 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.15651199).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ROBO4	NM_019055.6 linkuse as main transcript	c.2923G>C	p.Gly975Arg	missense_variant	17/18	ENST00000306534.8	NP_061928.4	Q8WZ75-1
ROBO4	NM_001301088.2 linkuse as main transcript	c.2488G>C	p.Gly830Arg	missense_variant	17/18		NP_001288017.1	Q8WZ75B4DYV8
ROBO4	XM_006718861.3 linkuse as main transcript	c.2809G>C	p.Gly937Arg	missense_variant	17/18		XP_006718924.1
ROBO4	XM_011542875.2 linkuse as main transcript	c.1597G>C	p.Gly533Arg	missense_variant	10/11		XP_011541177.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
ROBO4	ENST00000306534.8 linkuse as main transcript	c.2923G>C	p.Gly975Arg	missense_variant	17/18	1	NM_019055.6	ENSP00000304945.3	Q8WZ75-1
ROBO4	ENST00000534407.5 linkuse as main transcript	n.3130G>C		non_coding_transcript_exon_variant	4/5	1
ROBO4	ENST00000533054.5 linkuse as main transcript	c.2488G>C	p.Gly830Arg	missense_variant	17/18	2		ENSP00000437129.1	B4DYV8
ENSG00000254568	ENST00000524453.1 linkuse as main transcript	n.673+756C>G		intron_variant		3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000797

AC:

AN:

250976

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135750

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS 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:

1461822

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727222

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 08, 2024

The c.2923G>C (p.G975R) alteration is located in exon 17 (coding exon 17) of the ROBO4 gene. This alteration results from a G to C substitution at nucleotide position 2923, causing the glycine (G) at amino acid position 975 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.30

CADD

Benign

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.096

T;T

Eigen

Benign

-0.25

Eigen_PC

Benign

-0.14

FATHMM_MKL

Benign

0.63

LIST_S2

Benign

0.77

T;T

M_CAP

Benign

0.019

MetaRNN

Benign

0.16

T;T

MetaSVM

Benign

-0.95

MutationAssessor

Uncertain

2.6

M;.

PrimateAI

Benign

0.39

PROVEAN

Benign

-0.60

N;N

REVEL

Benign

0.053

Sift

Benign

0.094

T;T

Sift4G

Benign

0.11

T;T

Polyphen

0.12

B;.

Vest4

0.36

MutPred

0.23

Gain of MoRF binding (P = 0.0527);.;

MVP

0.79

MPC

0.46

ClinPred

0.80

GERP RS

4.3

Varity_R

0.080

gMVP

0.10

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over