chr17-28547304-G-A

Variant names:

• chr17-28547304-G-A
• rs1459531832
• NM_005148.4:c.716C>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005148.4(UNC119):​c.716C>T​(p.Thr239Ile) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: UNC119 NM_005148.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.38

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15507069).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UNC119	NM_005148.4	c.716C>T	p.Thr239Ile	missense_variant	Exon 5 of 5	ENST00000335765.9	NP_005139.1
UNC119	NM_001330166.2	c.431C>T	p.Thr144Ile	missense_variant	Exon 6 of 6		NP_001317095.1
UNC119	NM_054035.2	c.*320C>T		3_prime_UTR_variant	Exon 4 of 4		NP_473376.1
UNC119	XM_011525459.3	c.*499C>T		3_prime_UTR_variant	Exon 3 of 3		XP_011523761.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UNC119	ENST00000335765.9	c.716C>T	p.Thr239Ile	missense_variant	Exon 5 of 5	1	NM_005148.4	ENSP00000337040.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1461826 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727220

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Nov 13, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 239 of the UNC119 protein (p.Thr239Ile). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with UNC119-related conditions. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.049	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.58	D;T
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.064
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.77	T;T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.16	T;T
MetaSVM	Benign	-0.68	T
MutationAssessor	Benign	0.90	L;.
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-2.1	N;.
REVEL	Benign	0.23
Sift	Benign	0.053	T;.
Sift4G	Uncertain	0.023	D;D
Polyphen		0.11	B;.
Vest4		0.12
MutPred		0.25		Loss of glycosylation at T239 (P = 0.0248);.;
MVP		0.76
MPC		0.45
ClinPred		0.74	D
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.17
gMVP		0.31

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: rs1459531832; hg19: chr17-26874322;