10-71286698-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_170744.5(UNC5B):c.562C>G(p.Leu188Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: UNC5B NM_170744.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.16

Genes affected

UNC5B (HGNC:12568): (unc-5 netrin receptor B) This gene encodes a member of the netrin family of receptors. This particular protein mediates the repulsive effect of netrin-1 and is a vascular netrin receptor. This encoded protein is also in a group of proteins called dependence receptors (DpRs) which are involved in pro- and anti-apoptotic processes. Many DpRs are involved in embryogenesis and in cancer progression. Two alternatively spliced transcript variants have been described for this gene. [provided by RefSeq, Oct 2011]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.842

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UNC5B	NM_170744.5	c.562C>G	p.Leu188Val	missense_variant	5/17	ENST00000335350.10
UNC5B	NM_001244889.2	c.562C>G	p.Leu188Val	missense_variant	5/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UNC5B	ENST00000335350.10	c.562C>G	p.Leu188Val	missense_variant	5/17	1	NM_170744.5	P4
UNC5B	ENST00000373192.4	c.562C>G	p.Leu188Val	missense_variant	5/16	1		A1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

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 30, 2024

The c.562C>G (p.L188V) alteration is located in exon 5 (coding exon 5) of the UNC5B gene. This alteration results from a C to G substitution at nucleotide position 562, causing the leucine (L) at amino acid position 188 to be replaced by a valine (V). 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	0.26
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.030
Cadd	Pathogenic	27
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.46	T;.
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Benign	0.070	D
MetaRNN	Pathogenic	0.84	D;D
MetaSVM	Uncertain	-0.19	T
MutationAssessor	Pathogenic	3.3	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-2.8	D;D
REVEL	Uncertain	0.35
Sift	Uncertain	0.0070	D;D
Sift4G	Uncertain	0.0040	D;D
Polyphen		1.0	D;D
Vest4		0.81
MutPred		0.58		Gain of methylation at K189 (P = 0.0335);Gain of methylation at K189 (P = 0.0335);
MVP		0.66
MPC		0.64
ClinPred		0.98	D
GERP RS		5.4
Varity_R		0.61
gMVP		0.50

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: chr10-73046455;