rs199714731

Positions:

• chr17-28552493-C-A
• chr17-28552493-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_005148.4(UNC119):​c.65G>T​(p.Gly22Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00118 in 1,570,244 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0064 (12 hom., cov: 31)
  • Exomes 𝑓: 0.00062 (5 hom.)
• Consequence: UNC119 NM_005148.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1 B:5
• Conservation: PhyloP100: 2.53

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003015697).
• BP6: Variant 17-28552493-C-A is Benign according to our data. Variant chr17-28552493-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 88737.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-28552493-C-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00638 (971/152248) while in subpopulation AFR AF= 0.022 (916/41572). AF 95% confidence interval is 0.0208. There are 12 homozygotes in gnomad4. There are 482 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 971 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UNC119	NM_005148.4	c.65G>T	p.Gly22Val	missense_variant	1/5	ENST00000335765.9
UNC119	NM_054035.2	c.65G>T	p.Gly22Val	missense_variant	1/4
UNC119	XM_011525459.3	c.65G>T	p.Gly22Val	missense_variant	1/3
UNC119	NM_001330166.2	c.-249G>T		5_prime_UTR_variant	1/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UNC119	ENST00000335765.9	c.65G>T	p.Gly22Val	missense_variant	1/5	1	NM_005148.4	P1

Frequencies

GnomAD3 genomes AF: 0.00632 AC: 962 AN: 152142 Hom.: 11 Cov.: 31

Gnomad AFR AF: 0.0219

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00268

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00525

GnomAD3 exomes AF: 0.00160 AC: 290 AN: 181372 Hom.: 4 AF XY: 0.00132 AC XY: 135 AN XY: 102142

Gnomad AFR exome AF: 0.0286

Gnomad AMR exome AF: 0.00166

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000153

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000123

Gnomad OTH exome AF: 0.00217

GnomAD4 exome AF: 0.000618 AC: 877 AN: 1417996 Hom.: 5 Cov.: 31 AF XY: 0.000558 AC XY: 393 AN XY: 704522

Gnomad4 AFR exome AF: 0.0204

Gnomad4 AMR exome AF: 0.00169

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000968

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000855

Gnomad4 OTH exome AF: 0.00134

GnomAD4 genome AF: 0.00638 AC: 971 AN: 152248 Hom.: 12 Cov.: 31 AF XY: 0.00648 AC XY: 482 AN XY: 74434

Gnomad4 AFR AF: 0.0220

Gnomad4 AMR AF: 0.00268

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00520

Alfa AF: 0.00223 Hom.: 1

Bravo AF: 0.00722

ESP6500AA AF: 0.0142 AC: 49

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00173 AC: 197

Asia WGS AF: 0.00116 AC: 4 AN: 3462

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1 Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Idiopathic CD4 lymphocytopenia Pathogenic:1 Benign:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 09, 2012	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 28, 2015	- -

Cone-rod dystrophy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 22, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.17	T;.;T
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.40
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.75	T;T;T
MetaRNN	Benign	0.0030	T;T;T
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	1.1	L;L;.
MutationTaster	Benign	0.61	D;D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-0.98	N;N;N
REVEL	Benign	0.14
Sift	Uncertain	0.021	D;D;D
Sift4G	Uncertain	0.048	D;D;D
Polyphen		0.13	B;.;.
Vest4		0.17
MVP		0.57
MPC		0.61
ClinPred		0.017	T
GERP RS		2.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.058
gMVP		0.72

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: rs199714731; hg19: chr17-26879511; COSMIC: COSV99257150; COSMIC: COSV99257150;