rs764038221

Variant names:

• chr11-124887732-C-A
• rs764038221
• NM_019055.6:c.2056+1G>T

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Likely pathogenic. The variant received 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, intron 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, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 2.47
• Publications: 4 publications found

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, MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, G2P

ENSG00000254568 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.035714287 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 VariationId is 560404.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_019055.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ROBO4	NM_019055.6	MANE Select	c.2056+1G>T		splice_donor intron	N/A	NP_061928.4
	ROBO4	NM_001441183.1		c.2056+1G>T		splice_donor intron	N/A	NP_001428112.1
	ROBO4	NM_001301088.2		c.1621+1G>T		splice_donor intron	N/A	NP_001288017.1	B4DYV8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ROBO4	ENST00000306534.8	TSL:1 MANE Select	c.2056+1G>T		splice_donor intron	N/A	ENSP00000304945.3	Q8WZ75-1
	ROBO4	ENST00000534407.5	TSL:1	n.1733G>T		non_coding_transcript_exon	Exon 3 of 5
	ROBO4	ENST00000877825.1		c.2056+1G>T		splice_donor intron	N/A	ENSP00000547884.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Aortic valve disease 3 (1)
1	-	-	Bicuspid aortic valve;C0856747:Ascending tubular aorta aneurysm (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		2.5
GERP RS		5.0
Mutation Taster		=1/99	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs764038221; hg19: chr11-124757628;