chrX-118975175-C-G

Variant names:

• chrX-118975175-C-G
• rs768753376
• NM_001031855.3:c.395C>G

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001031855.3(LONRF3):​c.395C>G​(p.Ala132Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000122 in 1,062,727 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 8 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: not found (cov: 24)
  • Exomes 𝑓: 0.000012 (0 hom. 8 hem.)
• Consequence: LONRF3 NM_001031855.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0200

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]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.042517334).
• BS2: High Hemizygotes in GnomAdExome4 at 8 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LONRF3	NM_001031855.3	c.395C>G	p.Ala132Gly	missense_variant	Exon 1 of 11	ENST00000371628.8	NP_001027026.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LONRF3	ENST00000371628.8	c.395C>G	p.Ala132Gly	missense_variant	Exon 1 of 11	1	NM_001031855.3	ENSP00000360690.3
LONRF3	ENST00000304778.11	c.395C>G	p.Ala132Gly	missense_variant	Exon 1 of 10	1		ENSP00000307732.7
LONRF3	ENST00000481285.5	n.395C>G		non_coding_transcript_exon_variant	Exon 1 of 11	2		ENSP00000435426.1
LONRF3	ENST00000439603.5	c.-188C>G		upstream_gene_variant		1		ENSP00000414519.1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD3 exomes AF: 0.0000524 AC: 6 AN: 114558 Hom.: 0 AF XY: 0.000105 AC XY: 4 AN XY: 38006

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000413

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000122 AC: 13 AN: 1062727 Hom.: 0 Cov.: 34 AF XY: 0.0000231 AC XY: 8 AN XY: 346357

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000256

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 24

ExAC AF: 0.0000568 AC: 6

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 28, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.395C>G (p.A132G) alteration is located in exon 1 (coding exon 1) of the LONRF3 gene. This alteration results from a C to G substitution at nucleotide position 395, causing the alanine (A) at amino acid position 132 to be replaced by a glycine (G). 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	0.080
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	5.3
DANN	Benign	0.83
DEOGEN2	Benign	0.0065	.;T
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.42	T;T
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.043	T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	0.81	L;L
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-0.30	N;N
REVEL	Benign	0.15
Sift	Benign	0.26	T;T
Sift4G	Benign	0.49	T;T
Polyphen		0.0	B;B
Vest4		0.040
MutPred		0.25		Gain of relative solvent accessibility (P = 0.0104);Gain of relative solvent accessibility (P = 0.0104);
MVP		0.55
MPC		0.38
ClinPred		0.021	T
GERP RS		0.12
Varity_R		0.046
gMVP		0.26

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: rs768753376; hg19: chrX-118109138;