10-71285401-G-T

Variant names:

• chr10-71285401-G-T
• rs138539665
• NM_170744.5:c.524G>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_170744.5(UNC5B):​c.524G>T​(p.Arg175Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,453,038 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R175C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: UNC5B NM_170744.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 10.0
• Publications: 3 publications found

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

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.828

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_170744.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UNC5B	NM_170744.5	MANE Select	c.524G>T	p.Arg175Leu	missense	Exon 4 of 17	NP_734465.2
	UNC5B	NM_001244889.2		c.524G>T	p.Arg175Leu	missense	Exon 4 of 16	NP_001231818.1	Q8IZJ1-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UNC5B	ENST00000335350.10	TSL:1 MANE Select	c.524G>T	p.Arg175Leu	missense	Exon 4 of 17	ENSP00000334329.6	Q8IZJ1-1
	UNC5B	ENST00000373192.4	TSL:1	c.524G>T	p.Arg175Leu	missense	Exon 4 of 16	ENSP00000362288.4	Q8IZJ1-2
	UNC5B	ENST00000935474.1		c.524G>T	p.Arg175Leu	missense	Exon 4 of 17	ENSP00000605533.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD2 exomes AF: 0.00000435 AC: 1 AN: 229782 AF XY: 0.00000802

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1453038 Hom.: 0 Cov.: 32 AF XY: 0.00000277 AC XY: 2 AN XY: 722064

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33418

American (AMR) AF: 0.00 AC: 0 AN: 43616

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25890

East Asian (EAS) AF: 0.00 AC: 0 AN: 39400

South Asian (SAS) AF: 0.0000119 AC: 1 AN: 84384

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51574

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5756

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1108986

Other (OTH) AF: 0.00 AC: 0 AN: 60014

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000000770867), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 34

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Pathogenic	0.21
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.48	T
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.054	D
MetaRNN	Pathogenic	0.83	D
MetaSVM	Benign	-0.44	T
MutationAssessor	Benign	1.9	L
PhyloP100		10
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-5.6	D
REVEL	Uncertain	0.59
Sift	Benign	0.067	T
Sift4G	Benign	0.086	T
Polyphen		0.94	P
Vest4		0.84
MutPred		0.54		Loss of disorder (P = 0.1362)
MVP		0.91
MPC		0.22
ClinPred		0.98	D
GERP RS		4.8
Varity_R		0.47
gMVP		0.70
Mutation Taster		=43/57	disease causing

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

Other links and lift over

dbSNP: rs138539665; hg19: chr10-73045158;