rs34585936

Variant names:

• chr4-95170263-C-T
• rs34585936
• NM_003728.4:c.2521G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate 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 (★).

• 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, single submitter B:2
• Conservation: PhyloP100: 7.91
• Publications: 20 publications found

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

Our verdict: Benign. The variant received -14 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 VariationId is 2654955.Status of the report is criteria_provided_single_submitter, 1 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 40 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003728.4. 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
	UNC5C	NM_003728.4	MANE Select	c.2521G>A	p.Ala841Thr	missense	Exon 15 of 16	NP_003719.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UNC5C	ENST00000453304.6	TSL:1 MANE Select	c.2521G>A	p.Ala841Thr	missense	Exon 15 of 16	ENSP00000406022.1	O95185-1

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

GnomAD2 exomes AF: 0.0199 AC: 5003 AN: 251442 AF XY: 0.0201

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 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

African (AFR) AF: 0.00544 AC: 182 AN: 33480

American (AMR) AF: 0.0204 AC: 912 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0542 AC: 1416 AN: 26136

East Asian (EAS) AF: 0.0409 AC: 1623 AN: 39700

South Asian (SAS) AF: 0.0159 AC: 1368 AN: 86256

European-Finnish (FIN) AF: 0.00270 AC: 144 AN: 53418

Middle Eastern (MID) AF: 0.0352 AC: 203 AN: 5764

European-Non Finnish (NFE) AF: 0.0194 AC: 21578 AN: 1112008

Other (OTH) AF: 0.0250 AC: 1509 AN: 60390

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

African (AFR) AF: 0.00556 AC: 231 AN: 41550

American (AMR) AF: 0.0332 AC: 508 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0533 AC: 185 AN: 3468

East Asian (EAS) AF: 0.0418 AC: 216 AN: 5162

South Asian (SAS) AF: 0.0185 AC: 89 AN: 4818

European-Finnish (FIN) AF: 0.00169 AC: 18 AN: 10622

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.0191 AC: 1301 AN: 68008

Other (OTH) AF: 0.0383 AC: 81 AN: 2116

Alfa AF: 0.0206 Hom.: 151

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

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	UNC5C-related disorder (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D
MetaRNN	Benign	0.0083	T
MetaSVM	Benign	-0.88	T
MutationAssessor	Uncertain	2.9	M
PhyloP100		7.9
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-3.7	D
REVEL	Uncertain	0.33
Sift	Uncertain	0.0020	D
Sift4G	Benign	0.14	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
Mutation Taster		=87/13	polymorphism (auto)

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

Other links and lift over

dbSNP: rs34585936; hg19: chr4-96091414; COSMIC: COSV106601303;