rs267607166

Positions:

chr17-28552389-T-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_005148.4(UNC119):c.169A>T(p.Lys57*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000225 in 1,551,476 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.00015 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00023 ( 1 hom. )

Consequence

UNC119
NM_005148.4 stop_gained

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts P:1U:2

Conservation

PhyloP100: 2.60

Variant links:

Genes affected

UNC119 (HGNC:12565): (unc-119 lipid binding chaperone) This gene is specifically expressed in the photoreceptors in the retina. The encoded product shares strong homology with the C. elegans unc119 protein and it can functionally complement the C. elegans unc119 mutation. It has been localized to the photoreceptor synapses in the outer plexiform layer of the retina, and suggested to play a role in the mechanism of photoreceptor neurotransmitter release through the synaptic vesicle cycle. Two transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, Jul 2008]

UNC119 links:

RSKR (HGNC:26314): (ribosomal protein S6 kinase related) Predicted to enable protein kinase activity. Predicted to be involved in protein phosphorylation. [provided by Alliance of Genome Resources, Apr 2022]

RSKR links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BS2

High AC in GnomAd4 at 23 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
UNC119	NM_005148.4 link	c.169A>T	p.Lys57*	stop_gained	1/5	ENST00000335765.9	NP_005139.1	Q13432-1
UNC119	NM_054035.2 link	c.169A>T	p.Lys57*	stop_gained	1/4		NP_473376.1	Q13432-2
UNC119	XM_011525459.3 link	c.169A>T	p.Lys57*	stop_gained	1/3		XP_011523761.1
UNC119	NM_001330166.2 link	c.-145A>T		5_prime_UTR_variant	1/6		NP_001317095.1	Q13432K7EN86

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
UNC119	ENST00000335765.9 link	c.169A>T	p.Lys57*	stop_gained	1/5	1	NM_005148.4	ENSP00000337040.3		Q13432-1

Frequencies

GnomAD3 genomes

AF:

0.000151

AC:

AN:

152022

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000377

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000265

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000855

AC:

AN:

152098

Hom.:

AF XY:

0.0000709

AC XY:

AN XY:

84626

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000415

Gnomad NFE exome

AF:

0.000161

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000233

AC:

326

AN:

1399454

Hom.:

Cov.:

AF XY:

0.000228

AC XY:

158

AN XY:

692786

show subpopulations

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:

0.0000124

Gnomad4 FIN exome

AF:

0.000705

Gnomad4 NFE exome

AF:

0.000266

Gnomad4 OTH exome

AF:

0.000171

GnomAD4 genome

AF:

0.000151

AC:

AN:

152022

Hom.:

Cov.:

AF XY:

0.000135

AC XY:

AN XY:

74252

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000377

Gnomad4 NFE

AF:

0.000265

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000137

Hom.:

Bravo

AF:

0.000140

ExAC

AF:

0.0000272

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Cone-rod dystrophy 24

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 01, 2000

- -

Cone-rod dystrophy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Oct 24, 2018

The UNC119 c.169A>T (p.Lys57Ter) variant is a stop-gained variant that has been reported in one patient with late-onset cone-rod dystrophy (CRD) in a heterozygous state (Kobayashi et al. 2000). The variant was also found in the patient's 36-year-old daughter who shared a history of seeing bright flashes with her mother but did not as yet have a clinical diagnosis of CRD (Kobayashi et al. 2000). The p.Lys57Ter variant was absent from 100 controls but is reported at a frequency of 0.000378 in the European (Finnish) population of the Genome Aggregation Database. Functional studies in transgenic mice showed age-dependent fundus lesions compared with controls. In addition, electroretinogram analysis showed significant reduction in b-wave in transgenic mice older than one year compared to controls, light microscopy analysis showed changes to the retina, and electron microscopy showed changes consistent with retinal degeneration affecting the photoreceptor ribbon synapses (Kobayashi et al. 2000). Due to the potential impact of stop-gained variants and the evidence from the literature, the p.Lys57Ter variant is classified as a variant of unknown significance but suspicious for pathogenicity for cone-rod dystrophy. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 18, 2024

This sequence change creates a premature translational stop signal (p.Lys57*) in the UNC119 gene. It is expected to result in an absent or disrupted protein product. However, the current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in UNC119 cause disease. This variant is present in population databases (rs267607166, gnomAD 0.04%). This premature translational stop signal has been observed in individual(s) with cone-rod dystrophy (PMID: 11006213). ClinVar contains an entry for this variant (Variation ID: 5882). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects UNC119 function (PMID: 11006213). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.42

BayesDel_noAF

Pathogenic

0.48

CADD

Pathogenic

DANN

Uncertain

0.99

Eigen

Uncertain

0.57

Eigen_PC

Uncertain

0.41

FATHMM_MKL

Uncertain

0.87

Vest4

0.61

GERP RS

3.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over