11-124885208-A-G

Variant summary

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

The NM_019055.6(ROBO4):c.2834T>C(p.Leu945Pro) 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. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ROBO4 NM_019055.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.210

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 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=0.15561113).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ROBO4	NM_019055.6	c.2834T>C	p.Leu945Pro	missense_variant	17/18	ENST00000306534.8
ROBO4	NM_001301088.2	c.2399T>C	p.Leu800Pro	missense_variant	17/18
ROBO4	XM_006718861.3	c.2720T>C	p.Leu907Pro	missense_variant	17/18
ROBO4	XM_011542875.2	c.1508T>C	p.Leu503Pro	missense_variant	10/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ROBO4	ENST00000306534.8	c.2834T>C	p.Leu945Pro	missense_variant	17/18	1	NM_019055.6	P1
ROBO4	ENST00000534407.5	n.3041T>C		non_coding_transcript_exon_variant	4/5	1
	ENST00000524453.1	n.673+845A>G		intron_variant, non_coding_transcript_variant		3
ROBO4	ENST00000533054.5	c.2399T>C	p.Leu800Pro	missense_variant	17/18	2

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

Jul 11, 2023

The c.2834T>C (p.L945P) alteration is located in exon 17 (coding exon 17) of the ROBO4 gene. This alteration results from a T to C substitution at nucleotide position 2834, causing the leucine (L) at amino acid position 945 to be replaced by a proline (P). 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	0.10
BayesDel_addAF	Uncertain	0.087	D
BayesDel_noAF	Benign	-0.11
Cadd	Benign	19
Dann	Uncertain	1.0
DEOGEN2	Benign	0.073	T;T
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.51
FATHMM_MKL	Benign	0.33	N
LIST_S2	Benign	0.42	T;T
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.16	T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.8	L;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.050	N;N
REVEL	Uncertain	0.31
Sift	Benign	0.097	T;T
Sift4G	Benign	0.21	T;T
Polyphen		0.011	B;.
Vest4		0.46
MutPred		0.65		Gain of disorder (P = 0.005);.;
MVP		0.37
MPC		0.43
ClinPred		0.13	T
GERP RS		2.5
Varity_R		0.074
gMVP		0.025

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: chr11-124755104;