rs34875919

Positions:

• chr4-95250530-A-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_003728.4(UNC5C):​c.732T>C​(p.Ile244Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0547 in 1,613,924 control chromosomes in the GnomAD database, including 2,744 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.046 (196 hom., cov: 32)
  • Exomes 𝑓: 0.056 (2548 hom.)
• Consequence: UNC5C NM_003728.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.28

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP7: Synonymous conserved (PhyloP=-2.28 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0813 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
UNC5C	NM_003728.4	c.732T>C	p.Ile244Ile	synonymous_variant	5/16	ENST00000453304.6	NP_003719.3
UNC5C	XM_005263321.4	c.732T>C	p.Ile244Ile	synonymous_variant	5/17		XP_005263378.1
UNC5C	XM_047416345.1	c.-370T>C		5_prime_UTR_variant	6/18		XP_047272301.1
UNC5C	XM_047416346.1	c.-370T>C		5_prime_UTR_variant	7/19		XP_047272302.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
UNC5C	ENST00000453304.6	c.732T>C	p.Ile244Ile	synonymous_variant	5/16	1	NM_003728.4	ENSP00000406022.1
UNC5C	ENST00000513796.5	c.732T>C	p.Ile244Ile	synonymous_variant	5/14	1		ENSP00000426924.1
UNC5C	ENST00000506749.5	c.732T>C	p.Ile244Ile	synonymous_variant	5/11	1		ENSP00000426153.1
UNC5C	ENST00000504962.1	c.732T>C	p.Ile244Ile	synonymous_variant	5/6	2		ENSP00000425117.1

Frequencies

GnomAD3 genomes AF: 0.0460 AC: 7002 AN: 152066 Hom.: 193 Cov.: 32

Gnomad AFR AF: 0.0226

Gnomad AMI AF: 0.0954

Gnomad AMR AF: 0.0434

Gnomad ASJ AF: 0.0605

Gnomad EAS AF: 0.000966

Gnomad SAS AF: 0.0879

Gnomad FIN AF: 0.0759

Gnomad MID AF: 0.0886

Gnomad NFE AF: 0.0552

Gnomad OTH AF: 0.0446

GnomAD3 exomes AF: 0.0515 AC: 12953 AN: 251360 Hom.: 434 AF XY: 0.0545 AC XY: 7407 AN XY: 135840

Gnomad AFR exome AF: 0.0220

Gnomad AMR exome AF: 0.0270

Gnomad ASJ exome AF: 0.0623

Gnomad EAS exome AF: 0.000924

Gnomad SAS exome AF: 0.0856

Gnomad FIN exome AF: 0.0792

Gnomad NFE exome AF: 0.0558

Gnomad OTH exome AF: 0.0557

GnomAD4 exome AF: 0.0556 AC: 81205 AN: 1461740 Hom.: 2548 Cov.: 31 AF XY: 0.0569 AC XY: 41372 AN XY: 727184

Gnomad4 AFR exome AF: 0.0214

Gnomad4 AMR exome AF: 0.0290

Gnomad4 ASJ exome AF: 0.0622

Gnomad4 EAS exome AF: 0.000353

Gnomad4 SAS exome AF: 0.0845

Gnomad4 FIN exome AF: 0.0744

Gnomad4 NFE exome AF: 0.0561

Gnomad4 OTH exome AF: 0.0572

GnomAD4 genome AF: 0.0462 AC: 7029 AN: 152184 Hom.: 196 Cov.: 32 AF XY: 0.0479 AC XY: 3565 AN XY: 74386

Gnomad4 AFR AF: 0.0229

Gnomad4 AMR AF: 0.0433

Gnomad4 ASJ AF: 0.0605

Gnomad4 EAS AF: 0.000969

Gnomad4 SAS AF: 0.0882

Gnomad4 FIN AF: 0.0759

Gnomad4 NFE AF: 0.0552

Gnomad4 OTH AF: 0.0493

Alfa AF: 0.0520 Hom.: 123

Bravo AF: 0.0417

Asia WGS AF: 0.0580 AC: 203 AN: 3478

EpiCase AF: 0.0592

EpiControl AF: 0.0578

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	1.3
DANN	Benign	0.78

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: rs34875919; hg19: chr4-96171681;