11-124885142-C-A

Position:

• chr11-124885142-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_019055.6(ROBO4):​c.2900G>T​(p.Ser967Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 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)
• Consequence: ROBO4 NM_019055.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.612

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 (HGNC:):

ACMG classification

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=0.10030559).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ROBO4	NM_019055.6	c.2900G>T	p.Ser967Ile	missense_variant	17/18	ENST00000306534.8	NP_061928.4
ROBO4	NM_001301088.2	c.2465G>T	p.Ser822Ile	missense_variant	17/18		NP_001288017.1
ROBO4	XM_006718861.3	c.2786G>T	p.Ser929Ile	missense_variant	17/18		XP_006718924.1
ROBO4	XM_011542875.2	c.1574G>T	p.Ser525Ile	missense_variant	10/11		XP_011541177.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ROBO4	ENST00000306534.8	c.2900G>T	p.Ser967Ile	missense_variant	17/18	1	NM_019055.6	ENSP00000304945.3
ROBO4	ENST00000534407.5	n.3107G>T		non_coding_transcript_exon_variant	4/5	1
ROBO4	ENST00000533054.5	c.2465G>T	p.Ser822Ile	missense_variant	17/18	2		ENSP00000437129.1
ENSG00000254568	ENST00000524453.1	n.673+779C>A		intron_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 24, 2024

The c.2900G>T (p.S967I) alteration is located in exon 17 (coding exon 17) of the ROBO4 gene. This alteration results from a G to T substitution at nucleotide position 2900, causing the serine (S) at amino acid position 967 to be replaced by an isoleucine (I). 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	0.13
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	5.0
DANN	Benign	0.94
DEOGEN2	Benign	0.17	T;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.092	N
LIST_S2	Benign	0.32	T;T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.10	T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.1	L;.
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-2.1	N;N
REVEL	Benign	0.029
Sift	Benign	0.031	D;D
Sift4G	Uncertain	0.017	D;D
Polyphen		0.070	B;.
Vest4		0.16
MutPred		0.24		Loss of disorder (P = 0.0193);.;
MVP		0.58
MPC		0.091
ClinPred		0.057	T
GERP RS		0.044
Varity_R		0.13
gMVP		0.035

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-124755038;