X-118975165-G-A

Variant names:

• chrX-118975165-G-A
• rs776496199
• NM_001031855.3:c.385G>A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_001031855.3(LONRF3):​c.385G>A​(p.Gly129Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000298 in 1,173,696 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 22 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 Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0000088 (0 hom., 1 hem., cov: 24)
  • Exomes 𝑓: 0.000032 (0 hom. 21 hem.)
• Consequence: LONRF3 NM_001031855.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.214

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.033291608).
• BP6: Variant X-118975165-G-A is Benign according to our data. Variant chrX-118975165-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 3867676.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Hemizygotes in GnomAdExome4 at 21 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LONRF3	NM_001031855.3	c.385G>A	p.Gly129Ser	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.385G>A	p.Gly129Ser	missense_variant	Exon 1 of 11	1	NM_001031855.3	ENSP00000360690.3
LONRF3	ENST00000304778.11	c.385G>A	p.Gly129Ser	missense_variant	Exon 1 of 10	1		ENSP00000307732.7
LONRF3	ENST00000481285.5	n.385G>A		non_coding_transcript_exon_variant	Exon 1 of 11	2		ENSP00000435426.1
LONRF3	ENST00000439603.5	c.-198G>A		upstream_gene_variant		1		ENSP00000414519.1

Frequencies

GnomAD3 genomes AF: 0.00000884 AC: 1 AN: 113105 Hom.: 0 Cov.: 24 AF XY: 0.0000284 AC XY: 1 AN XY: 35261

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000357

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000178 AC: 2 AN: 112122 Hom.: 0 AF XY: 0.0000262 AC XY: 1 AN XY: 38184

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: 0.000139

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000321 AC: 34 AN: 1060546 Hom.: 0 Cov.: 34 AF XY: 0.0000607 AC XY: 21 AN XY: 346088

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: 0.000494

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000728

Gnomad4 OTH exome AF: 0.0000672

GnomAD4 genome AF: 0.00000884 AC: 1 AN: 113150 Hom.: 0 Cov.: 24 AF XY: 0.0000283 AC XY: 1 AN XY: 35316

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000358

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000416

ExAC AF: 0.0000482 AC: 5

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Dec 17, 2024

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	1.1
DANN	Benign	0.82
DEOGEN2	Benign	0.0072	.;T
FATHMM_MKL	Benign	0.050	N
LIST_S2	Benign	0.57	T;T
M_CAP	Uncertain	0.19	D
MetaRNN	Benign	0.033	T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-0.14	N;N
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-0.55	N;N
REVEL	Benign	0.13
Sift	Benign	0.74	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0	B;B
Vest4		0.033
MutPred		0.25		Gain of glycosylation at G129 (P = 0.0066);Gain of glycosylation at G129 (P = 0.0066);
MVP		0.52
MPC		0.38
ClinPred		0.021	T
GERP RS		1.2
Varity_R		0.036
gMVP		0.27

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: rs776496199; hg19: chrX-118109128; COSMIC: COSV100504795; COSMIC: COSV100504795;