Genetic Variant UNC119:p.Lys57Gln (chr17-28552389-T-G) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_005148.4(UNC119):c.169A>C(p.Lys57Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000715 in 1,399,454 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

UNC119
NM_005148.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.60

Publications

0 publications found

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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.27339315).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UNC119	NM_005148.4 link	c.169A>C	p.Lys57Gln	missense_variant	Exon 1 of 5	ENST00000335765.9	NP_005139.1	Q13432-1
UNC119	NM_054035.2 link	c.169A>C	p.Lys57Gln	missense_variant	Exon 1 of 4		NP_473376.1	Q13432-2
UNC119	XM_011525459.3 link	c.169A>C	p.Lys57Gln	missense_variant	Exon 1 of 3		XP_011523761.1
UNC119	NM_001330166.2 link	c.-145A>C		5_prime_UTR_variant	Exon 1 of 6		NP_001317095.1	Q13432K7EN86

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UNC119	ENST00000335765.9 link	c.169A>C	p.Lys57Gln	missense_variant	Exon 1 of 5	1	NM_005148.4	ENSP00000337040.3		Q13432-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.15e-7

AC:

AN:

1399454

Hom.:

Cov.:

AF XY:

0.00000144

AC XY:

AN XY:

692786

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31992

American (AMR)

AF:

0.00

AC:

AN:

37680

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25238

East Asian (EAS)

AF:

0.00

AC:

AN:

36930

South Asian (SAS)

AF:

0.00

AC:

AN:

80830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

35452

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4708

European-Non Finnish (NFE)

AF:

9.19e-7

AC:

AN:

1088276

Other (OTH)

AF:

0.00

AC:

AN:

58348

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.055

BayesDel_noAF

Benign

-0.32

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.25

T;.;T

Eigen

Benign

-0.32

Eigen_PC

Benign

-0.17

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.74

T;T;T

M_CAP

Pathogenic

0.80

MetaRNN

Benign

0.27

T;T;T

MetaSVM

Benign

-0.84

MutationAssessor

Benign

1.6

L;L;.

PhyloP100

2.6

PrimateAI

Pathogenic

0.91

PROVEAN

Benign

-1.5

N;N;N

REVEL

Benign

0.19

Sift

Benign

0.13

T;T;T

Sift4G

Benign

0.24

T;T;T

Polyphen

0.036

B;.;.

Vest4

0.24

MutPred

0.21

Loss of methylation at K57 (P = 0.0011);Loss of methylation at K57 (P = 0.0011);Loss of methylation at K57 (P = 0.0011);

MVP

0.69

MPC

0.45

ClinPred

0.65

GERP RS

3.5

PromoterAI

-0.26

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.42

gMVP

0.44

Mutation Taster

=78/22

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over