Variant X-118975342-G-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_001031855.3(LONRF3):c.562G>T(p.Ala188Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000141 in 1,208,710 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. 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 Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000088 ( 0 hom., 0 hem., cov: 25)

Exomes 𝑓: 0.000015 ( 0 hom. 3 hem. )

Consequence

LONRF3
NM_001031855.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.206

Variant links:

Genes affected

LONRF3 (HGNC:21152): (LON peptidase N-terminal domain and ring finger 3) The protein encoded by this gene contains a RING finger domain, a motif present in a variety of functionally distinct proteins and known to be involved in protein-protein and protein-DNA interactions. Multiple alternatively spliced transcript variants have been suggested, but their full length natures are not clear. [provided by RefSeq, Jul 2008]

LONRF3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.12810254).

BS2

High Hemizygotes in GnomAdExome4 at 3 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LONRF3	NM_001031855.3 linkuse as main transcript	c.562G>T	p.Ala188Ser	missense_variant	1/11	ENST00000371628.8	NP_001027026.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LONRF3	ENST00000371628.8 linkuse as main transcript	c.562G>T	p.Ala188Ser	missense_variant	1/11	1	NM_001031855.3	ENSP00000360690	P1	Q496Y0-1
LONRF3	ENST00000304778.11 linkuse as main transcript	c.562G>T	p.Ala188Ser	missense_variant	1/10	1		ENSP00000307732		Q496Y0-2
LONRF3	ENST00000481285.5 linkuse as main transcript	c.562G>T	p.Ala188Ser	missense_variant, NMD_transcript_variant	1/11	2		ENSP00000435426		Q496Y0-3
LONRF3	ENST00000439603.5 linkuse as main transcript			upstream_gene_variant		1		ENSP00000414519

Frequencies

GnomAD3 genomes

AF:

0.00000885

AC:

AN:

113003

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

35171

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000920

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:

0.0000466

AC:

AN:

171777

Hom.:

AF XY:

0.00

AC XY:

AN XY:

62981

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000259

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:

0.000233

GnomAD4 exome

AF:

0.0000146

AC:

AN:

1095707

Hom.:

Cov.:

AF XY:

0.00000828

AC XY:

AN XY:

362237

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000256

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:

0.00000357

Gnomad4 OTH exome

AF:

0.0000870

GnomAD4 genome

AF:

0.00000885

AC:

AN:

113003

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

35171

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000920

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

Bravo

AF:

0.0000340

ExAC

AF:

0.0000167

AC:

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 submitter

clinical testing

Ambry Genetics

May 06, 2024

The c.562G>T (p.A188S) alteration is located in exon 1 (coding exon 1) of the LONRF3 gene. This alteration results from a G to T substitution at nucleotide position 562, causing the alanine (A) at amino acid position 188 to be replaced by a serine (S). 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

0.085

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.49

CADD

Benign

DANN

Benign

0.93

DEOGEN2

Benign

0.014

.;T

FATHMM_MKL

Benign

0.74

LIST_S2

Benign

0.58

T;T

M_CAP

Pathogenic

0.90

MetaRNN

Benign

0.13

T;T

MetaSVM

Benign

-0.88

MutationAssessor

Benign

0.32

N;N

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Pathogenic

0.84

PROVEAN

Benign

0.050

N;N

REVEL

Benign

0.12

Sift

Benign

0.52

T;T

Sift4G

Benign

0.85

T;T

Polyphen

0.025

B;B

Vest4

0.077

MutPred

0.38

Gain of phosphorylation at A188 (P = 0.0208);Gain of phosphorylation at A188 (P = 0.0208);

MVP

0.79

MPC

0.45

ClinPred

0.018

GERP RS

2.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.044

gMVP

0.25

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over