4-95170263-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_003728.4(UNC5C):c.2521G>A(p.Ala841Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0196 in 1,614,124 control chromosomes in the GnomAD database, including 424 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.017 (40 hom., cov: 32)
  • Exomes 𝑓: 0.020 (384 hom.)
• Consequence: UNC5C NM_003728.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 7.91

Genes affected

UNC5C (HGNC:12569): (unc-5 netrin receptor C) This gene product belongs to the UNC-5 family of netrin receptors. Netrins are secreted proteins that direct axon extension and cell migration during neural development. They are bifunctional proteins that act as attractants for some cell types and as repellents for others, and these opposite actions are thought to be mediated by two classes of receptors. The UNC-5 family of receptors mediate the repellent response to netrin; they are transmembrane proteins containing 2 immunoglobulin (Ig)-like domains and 2 type I thrombospondin motifs in the extracellular region. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0082755685).
• BP6: Variant 4-95170263-C-T is Benign according to our data. Variant chr4-95170263-C-T is described in ClinVar as [Benign]. Clinvar id is 2654955.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0174 (2649/152248) while in subpopulation EAS AF= 0.0418 (216/5162). AF 95% confidence interval is 0.0373. There are 40 homozygotes in gnomad4. There are 1249 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 36 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UNC5C	NM_003728.4	c.2521G>A	p.Ala841Thr	missense_variant	15/16	ENST00000453304.6
UNC5C	XM_005263321.4	c.2578G>A	p.Ala860Thr	missense_variant	16/17
UNC5C	XM_047416345.1	c.1477G>A	p.Ala493Thr	missense_variant	17/18
UNC5C	XM_047416346.1	c.1477G>A	p.Ala493Thr	missense_variant	18/19

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UNC5C	ENST00000453304.6	c.2521G>A	p.Ala841Thr	missense_variant	15/16	1	NM_003728.4	P1

Frequencies

GnomAD3 genomes AF: 0.0173 AC: 2635 AN: 152130 Hom.: 36 Cov.: 32

Gnomad AFR AF: 0.00560

Gnomad AMI AF: 0.0132

Gnomad AMR AF: 0.0333

Gnomad ASJ AF: 0.0533

Gnomad EAS AF: 0.0419

Gnomad SAS AF: 0.0180

Gnomad FIN AF: 0.00169

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0191

Gnomad OTH AF: 0.0320

GnomAD3 exomes AF: 0.0199 AC: 5003 AN: 251442 Hom.: 76 AF XY: 0.0201 AC XY: 2727 AN XY: 135896

Gnomad AFR exome AF: 0.00591

Gnomad AMR exome AF: 0.0196

Gnomad ASJ exome AF: 0.0537

Gnomad EAS exome AF: 0.0420

Gnomad SAS exome AF: 0.0150

Gnomad FIN exome AF: 0.00213

Gnomad NFE exome AF: 0.0197

Gnomad OTH exome AF: 0.0280

GnomAD4 exome AF: 0.0198 AC: 28935 AN: 1461876 Hom.: 384 Cov.: 34 AF XY: 0.0199 AC XY: 14443 AN XY: 727236

Gnomad4 AFR exome AF: 0.00544

Gnomad4 AMR exome AF: 0.0204

Gnomad4 ASJ exome AF: 0.0542

Gnomad4 EAS exome AF: 0.0409

Gnomad4 SAS exome AF: 0.0159

Gnomad4 FIN exome AF: 0.00270

Gnomad4 NFE exome AF: 0.0194

Gnomad4 OTH exome AF: 0.0250

GnomAD4 genome AF: 0.0174 AC: 2649 AN: 152248 Hom.: 40 Cov.: 32 AF XY: 0.0168 AC XY: 1249 AN XY: 74442

Gnomad4 AFR AF: 0.00556

Gnomad4 AMR AF: 0.0332

Gnomad4 ASJ AF: 0.0533

Gnomad4 EAS AF: 0.0418

Gnomad4 SAS AF: 0.0185

Gnomad4 FIN AF: 0.00169

Gnomad4 NFE AF: 0.0191

Gnomad4 OTH AF: 0.0383

Alfa AF: 0.0207 Hom.: 74

Bravo AF: 0.0195

TwinsUK AF: 0.0165 AC: 61

ALSPAC AF: 0.0195 AC: 75

ESP6500AA AF: 0.00726 AC: 32

ESP6500EA AF: 0.0201 AC: 173

ExAC AF: 0.0186 AC: 2257

Asia WGS AF: 0.0480 AC: 168 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jul 01, 2023

UNC5C: BS1, BS2 -

UNC5C-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 26, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.50
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.38
Cadd	Uncertain	25
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.11	T;T
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D;D
MetaRNN	Benign	0.0083	T;T
MetaSVM	Benign	-0.88	T
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.68	T
Sift4G	Benign	0.14	T;T
Polyphen		1.0	.;D
Vest4		0.30
MPC		0.82
ClinPred		0.017	T
GERP RS		5.5
Varity_R		0.51
gMVP		0.65

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: rs34585936; hg19: chr4-96091414;