11-124885137-T-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.2905A>C(p.Thr969Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,766 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. T969T) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: ROBO4 NM_019055.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0860

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=0.10575971).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ROBO4	NM_019055.6	c.2905A>C	p.Thr969Pro	missense_variant	17/18	ENST00000306534.8
ROBO4	NM_001301088.2	c.2470A>C	p.Thr824Pro	missense_variant	17/18
ROBO4	XM_006718861.3	c.2791A>C	p.Thr931Pro	missense_variant	17/18
ROBO4	XM_011542875.2	c.1579A>C	p.Thr527Pro	missense_variant	10/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ROBO4	ENST00000306534.8	c.2905A>C	p.Thr969Pro	missense_variant	17/18	1	NM_019055.6	P1
ROBO4	ENST00000534407.5	n.3112A>C		non_coding_transcript_exon_variant	4/5	1
	ENST00000524453.1	n.673+774T>G		intron_variant, non_coding_transcript_variant		3
ROBO4	ENST00000533054.5	c.2470A>C	p.Thr824Pro	missense_variant	17/18	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461766 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727198

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00000360

Gnomad4 OTH exome AF: 0.00

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 14, 2023

The c.2905A>C (p.T969P) alteration is located in exon 17 (coding exon 17) of the ROBO4 gene. This alteration results from a A to C substitution at nucleotide position 2905, causing the threonine (T) at amino acid position 969 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	0.086
BayesDel_addAF	Benign	-0.039	T
BayesDel_noAF	Benign	-0.29
Cadd	Benign	15
Dann	Benign	0.95
DEOGEN2	Benign	0.099	T;T
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.67
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.54	T;T
M_CAP	Benign	0.035	D
MetaRNN	Benign	0.11	T;T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	1.9	M;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.89	N;N
REVEL	Benign	0.18
Sift	Uncertain	0.011	D;D
Sift4G	Uncertain	0.053	T;T
Polyphen		0.17	B;.
Vest4		0.12
MutPred		0.22		Gain of loop (P = 0.0079);.;
MVP		0.72
MPC		0.27
ClinPred		0.23	T
GERP RS		4.0
Varity_R		0.30
gMVP		0.23

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: chr11-124755033;