8-12723159-C-A

Variant summary

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

The NM_152271.5(LONRF1):​c.2259G>T​(p.Leu753Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,613,972 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

LONRF1
NM_152271.5 missense

Scores

7
8
4

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.61
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
LONRF1NM_152271.5 linkc.2259G>T p.Leu753Phe missense_variant Exon 12 of 12 ENST00000398246.8 NP_689484.3 Q17RB8-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
LONRF1ENST00000398246.8 linkc.2259G>T p.Leu753Phe missense_variant Exon 12 of 12 5 NM_152271.5 ENSP00000381298.3 Q17RB8-1

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152130
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000724
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:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000803
AC:
2
AN:
248980
Hom.:
0
AF XY:
0.00000740
AC XY:
1
AN XY:
135186
show subpopulations
Gnomad AFR exome
AF:
0.000129
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:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1461842
Hom.:
0
Cov.:
30
AF XY:
0.00000138
AC XY:
1
AN XY:
727226
show subpopulations
Gnomad4 AFR exome
AF:
0.0000597
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
AF:
0.0000197
AC:
3
AN:
152130
Hom.:
0
Cov.:
33
AF XY:
0.0000269
AC XY:
2
AN XY:
74312
show subpopulations
Gnomad4 AFR
AF:
0.0000724
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000712
Hom.:
0
Bravo
AF:
0.0000416
ExAC
AF:
0.0000165
AC:
2

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Nov 10, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.2259G>T (p.L753F) alteration is located in exon 12 (coding exon 12) of the LONRF1 gene. This alteration results from a G to T substitution at nucleotide position 2259, causing the leucine (L) at amino acid position 753 to be replaced by a phenylalanine (F). 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
Pathogenic
0.62
BayesDel_addAF
Uncertain
0.10
D
BayesDel_noAF
Pathogenic
0.15
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Benign
0.089
T;.;T;T
Eigen
Pathogenic
0.78
Eigen_PC
Pathogenic
0.71
FATHMM_MKL
Uncertain
0.88
D
LIST_S2
Uncertain
0.92
D;.;D;D
M_CAP
Benign
0.048
D
MetaRNN
Uncertain
0.72
D;D;D;D
MetaSVM
Benign
-0.32
T
MutationAssessor
Pathogenic
3.0
M;.;.;.
PrimateAI
Uncertain
0.68
T
PROVEAN
Uncertain
-3.8
D;D;D;D
REVEL
Uncertain
0.35
Sift
Pathogenic
0.0
D;D;D;D
Sift4G
Pathogenic
0.0
D;D;D;D
Polyphen
1.0
D;.;.;.
Vest4
0.70
MutPred
0.63
Loss of helix (P = 0.079);.;.;.;
MVP
0.61
MPC
1.7
ClinPred
0.99
D
GERP RS
5.1
Varity_R
0.73
gMVP
0.50

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs747877739; hg19: chr8-12580668; API