8-35726202-C-T

Position:

• chr8-35726202-C-T

Variant summary

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

The NM_080872.4(UNC5D):​c.1354C>T​(p.Arg452Trp) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,668 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R452Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: UNC5D NM_080872.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.77

Genes affected

UNC5D (HGNC:18634): (unc-5 netrin receptor D) Predicted to enable netrin receptor activity. Involved in cell-cell adhesion via plasma-membrane adhesion molecules. Predicted to be located in cell surface and plasma membrane. Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UNC5D	NM_080872.4	c.1354C>T	p.Arg452Trp	missense_variant	10/17	ENST00000404895.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UNC5D	ENST00000404895.7	c.1354C>T	p.Arg452Trp	missense_variant	10/17	1	NM_080872.4	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461668 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727102

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: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000312 Hom.: 0

Bravo AF: 0.00000378

EpiCase AF: 0.0000545

EpiControl AF: 0.00

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

Feb 06, 2024

The c.1354C>T (p.R452W) alteration is located in exon 10 (coding exon 10) of the UNC5D gene. This alteration results from a C to T substitution at nucleotide position 1354, causing the arginine (R) at amino acid position 452 to be replaced by a tryptophan (W). 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	0.34
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.14
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.19	T;T;T;T;.;.
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.96	D;D;D;D;D;D
M_CAP	Benign	0.041	D
MetaRNN	Uncertain	0.69	D;D;D;D;D;D
MetaSVM	Benign	-0.51	T
MutationAssessor	Uncertain	2.2	M;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-3.0	D;D;D;D;D;D
REVEL	Benign	0.23
Sift	Uncertain	0.0090	D;D;D;D;D;D
Sift4G	Uncertain	0.021	D;D;D;D;D;D
Polyphen		1.0	D;.;.;D;D;D
Vest4		0.91
MutPred		0.41		.;.;.;Loss of disorder (P = 0.0267);.;.;
MVP		0.57
MPC		1.3
ClinPred		0.97	D
GERP RS		5.2
Varity_R		0.13
gMVP		0.74

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs868178712; hg19: chr8-35583720;