rs764038221

Positions:

• chr11-124887732-C-A
• chr11-124887732-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_Moderate PM2 PP5_Moderate

The NM_019055.6(ROBO4):​c.2056+1G>T variant causes a splice donor change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ROBO4 NM_019055.6 splice_donor
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 2.47

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]

(HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.035383597 fraction of the gene. Cryptic splice site detected, with MaxEntScore 4.7, offset of 33, new splice context is: gggGTgaga. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-124887732-C-A is Pathogenic according to our data. Variant chr11-124887732-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 560404.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ROBO4	NM_019055.6	c.2056+1G>T		splice_donor_variant		ENST00000306534.8	NP_061928.4
ROBO4	NM_001301088.2	c.1621+1G>T		splice_donor_variant			NP_001288017.1
ROBO4	XM_006718861.3	c.2056+1G>T		splice_donor_variant			XP_006718924.1
ROBO4	XM_011542875.2	c.730+1G>T		splice_donor_variant			XP_011541177.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ROBO4	ENST00000306534.8	c.2056+1G>T		splice_donor_variant		1	NM_019055.6	ENSP00000304945	P1
	ENST00000524453.1	n.687C>A		non_coding_transcript_exon_variant	2/2	3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Bicuspid aortic valve;C0856747:Ascending tubular aorta aneurysm Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

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

-

- -

Aortic valve disease 3 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 09, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.24
CADD	Pathogenic	34
DANN	Uncertain	0.99
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Uncertain	0.85	D
MutationTaster	Benign	1.0	D;D
GERP RS		5.0

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.92
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.45		Position offset: 46
DS_DL_spliceai		0.99		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs764038221; hg19: chr11-124757628;