3-77040793-T-A

Position:

• chr3-77040793-T-A

Variant summary

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

The NM_001395656.1(ROBO2):​c.8T>A​(p.Leu3Gln) 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. 13/18 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: ROBO2 NM_001395656.1 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.69

Genes affected

ROBO2 (HGNC:10250): (roundabout guidance receptor 2) The protein encoded by this gene belongs to the ROBO family, part of the immunoglobulin superfamily of proteins that are highly conserved from fly to human. The encoded protein is a transmembrane receptor for the slit homolog 2 protein and functions in axon guidance and cell migration. Mutations in this gene are associated with vesicoureteral reflux, characterized by the backward flow of urine from the bladder into the ureters or the kidney. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2014]

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=0.16819683).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ROBO2	NM_001395656.1	c.8T>A	p.Leu3Gln	missense_variant	1/28	ENST00000696593.1	NP_001382585.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ROBO2	ENST00000696593.1	c.8T>A	p.Leu3Gln	missense_variant	1/28		NM_001395656.1	ENSP00000512738	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 27, 2023

The c.8T>A (p.L3Q) alteration is located in exon 1 (coding exon 1) of the ROBO2 gene. This alteration results from a T to A substitution at nucleotide position 8, causing the leucine (L) at amino acid position 3 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 26, 2024

This sequence change replaces leucine, which is neutral and non-polar, with glutamine, which is neutral and polar, at codon 3 of the ROBO2 protein (p.Leu3Gln). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with ROBO2-related conditions. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt ROBO2 protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.66
BayesDel_addAF	Benign	-0.053	T
BayesDel_noAF	Benign	-0.31
CADD	Uncertain	25
DANN	Benign	0.97
DEOGEN2	Benign	0.095	T;.
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.046
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.57	T;T
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.17	T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.0	N;.
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.26	N;N
REVEL	Benign	0.17
Sift	Benign	0.031	D;D
Sift4G	Benign	0.11	T;T
Polyphen		0.39	B;P
Vest4		0.34
MutPred		0.61		Gain of disorder (P = 0.0239);Gain of disorder (P = 0.0239);
MVP		0.41
ClinPred		0.32	T
GERP RS		3.0
Varity_R		0.10

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: chr3-77089944;