Variant 11-124886622-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_019055.6(ROBO4):c.2636C>T(p.Ser879Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,792 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

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: 7.44

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:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.762

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
ROBO4	NM_019055.6 linkuse as main transcript	c.2636C>T	p.Ser879Leu	missense_variant	16/18	ENST00000306534.8
ROBO4	NM_001301088.2 linkuse as main transcript	c.2201C>T	p.Ser734Leu	missense_variant	16/18
ROBO4	XM_006718861.3 linkuse as main transcript	c.2522C>T	p.Ser841Leu	missense_variant	16/18
ROBO4	XM_011542875.2 linkuse as main transcript	c.1310C>T	p.Ser437Leu	missense_variant	9/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ROBO4	ENST00000306534.8 linkuse as main transcript	c.2636C>T	p.Ser879Leu	missense_variant	16/18	1	NM_019055.6	P1	Q8WZ75-1
	ENST00000524453.1 linkuse as main transcript	n.674-1097G>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000401

AC:

AN:

249316

Hom.:

AF XY:

0.00000740

AC XY:

AN XY:

135044

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000290

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:

1461792

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727202

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.:

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

Jan 17, 2024

The c.2636C>T (p.S879L) alteration is located in exon 16 (coding exon 16) of the ROBO4 gene. This alteration results from a C to T substitution at nucleotide position 2636, causing the serine (S) at amino acid position 879 to be replaced by a leucine (L). 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

Uncertain

0.40

BayesDel_addAF

Pathogenic

0.37

BayesDel_noAF

Pathogenic

0.38

Cadd

Pathogenic

Dann

Pathogenic

1.0

DEOGEN2

Uncertain

0.60

D;T

Eigen

Pathogenic

0.88

Eigen_PC

Pathogenic

0.84

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.96

D;D

M_CAP

Uncertain

0.13

MetaRNN

Pathogenic

0.76

D;D

MetaSVM

Pathogenic

0.83

MutationAssessor

Uncertain

2.9

M;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.68

PROVEAN

Uncertain

-3.6

D;D

REVEL

Pathogenic

0.66

Sift

Pathogenic

0.0

D;D

Sift4G

Uncertain

0.0030

D;D

Polyphen

1.0

D;.

Vest4

0.83

MutPred

0.19

Loss of phosphorylation at S879 (P = 0.0268);.;

MVP

0.97

MPC

0.14

ClinPred

0.97

GERP RS

4.9

Varity_R

0.57

gMVP

0.44

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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