11-124885061-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_019055.6(ROBO4):c.2981G>A(p.Cys994Tyr) 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ROBO4 NM_019055.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0680

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_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0614869).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ROBO4	NM_019055.6	c.2981G>A	p.Cys994Tyr	missense_variant	17/18	ENST00000306534.8
ROBO4	NM_001301088.2	c.2546G>A	p.Cys849Tyr	missense_variant	17/18
ROBO4	XM_006718861.3	c.2867G>A	p.Cys956Tyr	missense_variant	17/18
ROBO4	XM_011542875.2	c.1655G>A	p.Cys552Tyr	missense_variant	10/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ROBO4	ENST00000306534.8	c.2981G>A	p.Cys994Tyr	missense_variant	17/18	1	NM_019055.6	P1
ROBO4	ENST00000534407.5	n.3188G>A		non_coding_transcript_exon_variant	4/5	1
	ENST00000524453.1	n.673+698C>T		intron_variant, non_coding_transcript_variant		3
ROBO4	ENST00000533054.5	c.2546G>A	p.Cys849Tyr	missense_variant	17/18	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 6.84e-7 AC: 1 AN: 1461836 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727210

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: 8.99e-7

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

Jan 29, 2024

The c.2981G>A (p.C994Y) alteration is located in exon 17 (coding exon 17) of the ROBO4 gene. This alteration results from a G to A substitution at nucleotide position 2981, causing the cysteine (C) at amino acid position 994 to be replaced by a tyrosine (Y). 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	0.091
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.56
Cadd	Benign	8.5
Dann	Benign	0.86
DEOGEN2	Benign	0.056	T;T
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.69
FATHMM_MKL	Benign	0.032	N
LIST_S2	Benign	0.54	T;T
M_CAP	Benign	0.0079	T
MetaRNN	Benign	0.061	T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.4	L;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.48	N;N
REVEL	Benign	0.10
Sift	Benign	0.44	T;T
Sift4G	Benign	0.064	T;T
Polyphen		0.0	B;.
Vest4		0.11
MutPred		0.18		Gain of phosphorylation at C994 (P = 0.0084);.;
MVP		0.45
MPC		0.26
ClinPred		0.074	T
GERP RS		1.3
Varity_R		0.037
gMVP		0.027

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: chr11-124754957; COSMIC: COSV60623611; COSMIC: COSV60623611;