X-118975175-C-A

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001031855.3(LONRF3):​c.395C>A​(p.Ala132Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000941 in 1,062,727 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A132G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 9.4e-7 (0 hom. 0 hem.)
• Consequence: LONRF3 NM_001031855.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0200
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.083513886).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001031855.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LONRF3	NM_001031855.3	MANE Select	c.395C>A	p.Ala132Glu	missense	Exon 1 of 11	NP_001027026.1	Q496Y0-1
	LONRF3	NM_024778.5		c.395C>A	p.Ala132Glu	missense	Exon 1 of 10	NP_079054.3	A8K2D3
	LONRF3	NR_110311.1		n.562C>A		non_coding_transcript_exon	Exon 1 of 11

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LONRF3	ENST00000371628.8	TSL:1 MANE Select	c.395C>A	p.Ala132Glu	missense	Exon 1 of 11	ENSP00000360690.3	Q496Y0-1
	LONRF3	ENST00000304778.11	TSL:1	c.395C>A	p.Ala132Glu	missense	Exon 1 of 10	ENSP00000307732.7	Q496Y0-2
	LONRF3	ENST00000961937.1		c.395C>A	p.Ala132Glu	missense	Exon 1 of 10	ENSP00000631996.1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome AF: 9.41e-7 AC: 1 AN: 1062727 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 346357

African (AFR) AF: 0.00 AC: 0 AN: 25371

American (AMR) AF: 0.00 AC: 0 AN: 29195

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18760

East Asian (EAS) AF: 0.0000357 AC: 1 AN: 28012

South Asian (SAS) AF: 0.00 AC: 0 AN: 50699

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37163

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3552

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 825297

Other (OTH) AF: 0.00 AC: 0 AN: 44678

GnomAD4 genome Cov.: 24

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	7.5
DANN	Benign	0.75
DEOGEN2	Benign	0.0074	T
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.34	T
M_CAP	Uncertain	0.091	D
MetaRNN	Benign	0.084	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.81	L
PhyloP100		-0.020
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-0.44	N
REVEL	Benign	0.19
Sift	Benign	0.41	T
Sift4G	Benign	0.73	T
Polyphen		0.0010	B
Vest4		0.075
MutPred		0.24		Gain of relative solvent accessibility (P = 0.1012)
MVP		0.60
MPC		0.47
ClinPred		0.036	T
GERP RS		0.12
PromoterAI		0.041	Neutral
Varity_R		0.098
gMVP		0.40
Mutation Taster		=98/2	polymorphism

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

Other links and lift over

dbSNP: rs768753376; hg19: chrX-118109138; COSMIC: COSV107356646; COSMIC: COSV107356646;