rs267607166

chr17-28552389-T-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM4 BS2

The NM_005148.4(UNC119):c.169A>T(p.Lys57Ter) 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
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts P:1 U:2
• Conservation: PhyloP100: 2.60

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]

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM4: Stoplost variant in NM_005148.4 Downstream stopcodon found after 3 codons.
• BS2: High AC in GnomAd at 23 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UNC119	NM_005148.4	c.169A>T	p.Lys57Ter	stop_gained	1/5	ENST00000335765.9
UNC119	NM_054035.2	c.169A>T	p.Lys57Ter	stop_gained	1/4
UNC119	XM_011525459.3	c.169A>T	p.Lys57Ter	stop_gained	1/3
UNC119	NM_001330166.2	c.-145A>T		5_prime_UTR_variant	1/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UNC119	ENST00000335765.9	c.169A>T	p.Lys57Ter	stop_gained	1/5	1	NM_005148.4	P1

Frequencies

GnomAD3 genomes AF: 0.000151 AC: 23 AN: 152022 Hom.: 0 Cov.: 31

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: 13 AN: 152098 Hom.: 0 AF XY: 0.0000709 AC XY: 6 AN XY: 84626

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.: 1 Cov.: 31 AF XY: 0.000228 AC XY: 158 AN XY: 692786

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: 23 AN: 152022 Hom.: 0 Cov.: 31 AF XY: 0.000135 AC XY: 10 AN XY: 74252

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.: 0

Bravo AF: 0.000140

ExAC AF: 0.0000272 AC: 3

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

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

Invitae

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	D
BayesDel_noAF	Pathogenic	0.48
Cadd	Pathogenic	37
Dann	Uncertain	0.99
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.87	D
MutationTaster	Benign	1.0	A;A
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

Other links and lift over

dbSNP: rs267607166; hg19: chr17-26879407;