8-12725857-T-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_152271.5(LONRF1):​c.2033A>G​(p.Lys678Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 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)

Consequence

LONRF1
NM_152271.5 missense

Scores

1
18

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.02
Variant links:
Genes affected
LONRF1 (HGNC:26302): (LON peptidase N-terminal domain and ring finger 1) Predicted to enable metal ion binding activity. Predicted to be located in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.06250852).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
LONRF1NM_152271.5 linkuse as main transcriptc.2033A>G p.Lys678Arg missense_variant 11/12 ENST00000398246.8 NP_689484.3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
LONRF1ENST00000398246.8 linkuse as main transcriptc.2033A>G p.Lys678Arg missense_variant 11/125 NM_152271.5 ENSP00000381298 P1Q17RB8-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsFeb 21, 2024The c.2033A>G (p.K678R) alteration is located in exon 11 (coding exon 11) of the LONRF1 gene. This alteration results from a A to G substitution at nucleotide position 2033, causing the lysine (K) at amino acid position 678 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.064
BayesDel_addAF
Benign
-0.33
T
BayesDel_noAF
Benign
-0.71
CADD
Benign
15
DANN
Uncertain
0.99
DEOGEN2
Benign
0.0055
T;.;T;T
Eigen
Benign
-0.76
Eigen_PC
Benign
-0.72
FATHMM_MKL
Benign
0.52
D
LIST_S2
Benign
0.63
T;.;T;T
M_CAP
Benign
0.0033
T
MetaRNN
Benign
0.063
T;T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
0.28
N;.;.;.
MutationTaster
Benign
1.0
D;D;D
PrimateAI
Benign
0.25
T
PROVEAN
Benign
-0.61
N;N;N;N
REVEL
Benign
0.035
Sift
Benign
0.56
T;T;T;T
Sift4G
Benign
0.41
T;T;T;T
Polyphen
0.0
B;.;.;.
Vest4
0.12
MutPred
0.36
Loss of ubiquitination at K678 (P = 0.0127);.;.;.;
MVP
0.35
MPC
0.53
ClinPred
0.086
T
GERP RS
1.5
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.022
gMVP
0.33

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.030
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr8-12583366; API