8-35595598-C-T

Position:

• chr8-35595598-C-T

Variant summary

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

The NM_080872.4(UNC5D):​c.511C>T​(p.Pro171Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: UNC5D NM_080872.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.51

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.511C>T	p.Pro171Ser	missense_variant	4/17	ENST00000404895.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UNC5D	ENST00000404895.7	c.511C>T	p.Pro171Ser	missense_variant	4/17	1	NM_080872.4	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000936 Hom.: 0

Bravo AF: 0.00000378

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

Mar 29, 2023

The c.511C>T (p.P171S) alteration is located in exon 4 (coding exon 4) of the UNC5D gene. This alteration results from a C to T substitution at nucleotide position 511, causing the proline (P) at amino acid position 171 to be replaced by a serine (S). 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	0.24
BayesDel_addAF	Benign	0.0075	T
BayesDel_noAF	Benign	-0.23
CADD	Uncertain	24
DANN	Benign	0.95
DEOGEN2	Benign	0.044	T;T;T;T;.
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.92	D;D;D;D;D
M_CAP	Benign	0.027	D
MetaRNN	Uncertain	0.46	T;T;T;T;T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	0.81	L;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-0.69	N;N;N;N;N
REVEL	Benign	0.098
Sift	Benign	0.77	T;T;T;T;T
Sift4G	Benign	0.77	T;T;T;T;T
Polyphen		0.80	P;.;.;.;P
Vest4		0.68
MutPred		0.29		Gain of phosphorylation at P171 (P = 0.0337);Gain of phosphorylation at P171 (P = 0.0337);Gain of phosphorylation at P171 (P = 0.0337);Gain of phosphorylation at P171 (P = 0.0337);.;
MVP		0.10
MPC		0.58
ClinPred		0.62	D
GERP RS		5.9
Varity_R		0.073
gMVP		0.63

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: rs1819441181; hg19: chr8-35453116; COSMIC: COSV54769077;