5-176877575-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_133369.3(UNC5A):c.1507G>A(p.Val503Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0000158 in 1,458,490 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: UNC5A NM_133369.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.97

Genes affected

UNC5A (HGNC:12567): (unc-5 netrin receptor A) UNC5A belongs to a family of netrin-1 (MIM 601614) receptors thought to mediate the chemorepulsive effect of netrin-1 on specific axons. For more information on UNC5 proteins, see UNC5C (MIM 603610).[supplied by OMIM, Apr 2004]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, UNC5A
• BP4: Computational evidence support a benign effect (MetaRNN=0.24536896).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UNC5A	NM_133369.3	c.1507G>A	p.Val503Ile	missense_variant	10/15	ENST00000329542.9
UNC5A	XM_011534686.2	c.1675G>A	p.Val559Ile	missense_variant	11/14
UNC5A	XM_006714927.2	c.1507G>A	p.Val503Ile	missense_variant	10/13
UNC5A	XM_006714928.2	c.1675G>A	p.Val559Ile	missense_variant	11/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UNC5A	ENST00000329542.9	c.1507G>A	p.Val503Ile	missense_variant	10/15	1	NM_133369.3
UNC5A	ENST00000509580.2	c.1675G>A	p.Val559Ile	missense_variant	11/16	5		P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000804 AC: 2 AN: 248908 Hom.: 0 AF XY: 0.00000741 AC XY: 1 AN XY: 135008

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000582

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS 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: 0.0000158 AC: 23 AN: 1458490 Hom.: 0 Cov.: 33 AF XY: 0.0000165 AC XY: 12 AN XY: 725216

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000673

Gnomad4 ASJ exome AF: 0.0000384

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000162

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

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

Aug 08, 2022

The c.1507G>A (p.V503I) alteration is located in exon 10 (coding exon 10) of the UNC5A gene. This alteration results from a G to A substitution at nucleotide position 1507, causing the valine (V) at amino acid position 503 to be replaced by an isoleucine (I). 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	0.070
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.50
Cadd	Uncertain	24
Dann	Uncertain	0.99
DEOGEN2	Benign	0.10	T;.
Eigen	Benign	0.010
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.25	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.3	L;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-0.74	N;.
REVEL	Benign	0.081
Sift	Benign	0.16	T;.
Sift4G	Benign	0.20	T;.
Polyphen		0.12	B;.
Vest4		0.23
MutPred		0.68		Loss of sheet (P = 0.1158);.;
MVP		0.41
MPC		0.49
ClinPred		0.37	T
GERP RS		4.4
Varity_R		0.083
gMVP		0.32

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs755099198; hg19: chr5-176304576; COSMIC: COSV52838296; COSMIC: COSV52838296;