10-71213040-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_170744.5(UNC5B):c.55T>A(p.Trp19Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000791 in 1,264,034 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.9e-7 (0 hom.)
• Consequence: UNC5B NM_170744.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.24

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3369749).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UNC5B	NM_170744.5	c.55T>A	p.Trp19Arg	missense_variant	1/17	ENST00000335350.10
UNC5B	NM_001244889.2	c.55T>A	p.Trp19Arg	missense_variant	1/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UNC5B	ENST00000335350.10	c.55T>A	p.Trp19Arg	missense_variant	1/17	1	NM_170744.5	P4
UNC5B	ENST00000373192.4	c.55T>A	p.Trp19Arg	missense_variant	1/16	1		A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.91e-7 AC: 1 AN: 1264034 Hom.: 0 Cov.: 30 AF XY: 0.00000161 AC XY: 1 AN XY: 622550

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: 9.90e-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

Dec 13, 2021

The c.55T>A (p.W19R) alteration is located in exon 1 (coding exon 1) of the UNC5B gene. This alteration results from a T to A substitution at nucleotide position 55, causing the tryptophan (W) at amino acid position 19 to be replaced by an arginine (R). 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	0.21
BayesDel_addAF	Benign	-0.086	T
BayesDel_noAF	Benign	-0.36
Cadd	Pathogenic	27
Dann	Benign	0.96
DEOGEN2	Benign	0.15	T;.
Eigen	Uncertain	0.20
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.35	T;T
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.34	T;T
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	0.90	L;L
MutationTaster	Benign	0.67	D;D
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-1.8	N;N
REVEL	Benign	0.21
Sift	Benign	0.28	T;T
Sift4G	Benign	0.26	T;T
Polyphen		0.94	P;D
Vest4		0.33
MutPred		0.49		Gain of disorder (P = 0);Gain of disorder (P = 0);
MVP		0.75
MPC		0.28
ClinPred		0.58	D
GERP RS		4.4
Varity_R		0.31
gMVP		0.46

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

LitVar

Other links and lift over

dbSNP: rs1017635371; hg19: chr10-72972797;