X-118974920-C-A

Variant names:

• chrX-118974920-C-A
• NM_001031855.3:c.140C>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.140C>A​(p.Ala47Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000253 in 1,187,115 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A47S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000088 (0 hom., 1 hem., cov: 24)
  • Exomes 𝑓: 0.0000019 (0 hom. 0 hem.)
• Consequence: LONRF3 NM_001031855.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.07
• 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=0.10567093).

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.140C>A	p.Ala47Glu	missense	Exon 1 of 11	NP_001027026.1	Q496Y0-1
	LONRF3	NM_024778.5		c.140C>A	p.Ala47Glu	missense	Exon 1 of 10	NP_079054.3	A8K2D3
	LONRF3	NR_110311.1		n.307C>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.140C>A	p.Ala47Glu	missense	Exon 1 of 11	ENSP00000360690.3	Q496Y0-1
	LONRF3	ENST00000304778.11	TSL:1	c.140C>A	p.Ala47Glu	missense	Exon 1 of 10	ENSP00000307732.7	Q496Y0-2
	LONRF3	ENST00000961937.1		c.140C>A	p.Ala47Glu	missense	Exon 1 of 10	ENSP00000631996.1

Frequencies

GnomAD3 genomes AF: 0.00000883 AC: 1 AN: 113277 Hom.: 0 Cov.: 24

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: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000187

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000186 AC: 2 AN: 1073838 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 347392

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 25989

American (AMR) AF: 0.00 AC: 0 AN: 31747

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18836

East Asian (EAS) AF: 0.00 AC: 0 AN: 28866

South Asian (SAS) AF: 0.00 AC: 0 AN: 51117

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38074

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4083

European-Non Finnish (NFE) AF: 0.00000241 AC: 2 AN: 830048

Other (OTH) AF: 0.00 AC: 0 AN: 45078

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000000770867), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00000883 AC: 1 AN: 113277 Hom.: 0 Cov.: 24 AF XY: 0.0000282 AC XY: 1 AN XY: 35399

African (AFR) AF: 0.00 AC: 0 AN: 31233

American (AMR) AF: 0.00 AC: 0 AN: 10884

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2656

East Asian (EAS) AF: 0.00 AC: 0 AN: 3580

South Asian (SAS) AF: 0.00 AC: 0 AN: 2784

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6350

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 240

European-Non Finnish (NFE) AF: 0.0000187 AC: 1 AN: 53341

Other (OTH) AF: 0.00 AC: 0 AN: 1528

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	4.7
DANN	Benign	0.71
DEOGEN2	Benign	0.0061	T
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.56	T
M_CAP	Pathogenic	0.38	D
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.4	L
PhyloP100		1.1
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	0.47	N
REVEL	Benign	0.13
Sift	Benign	0.27	T
Sift4G	Benign	0.28	T
Polyphen		0.0	B
Vest4		0.046
MutPred		0.11		Gain of solvent accessibility (P = 0.0246)
MVP		0.44
MPC		0.44
ClinPred		0.11	T
GERP RS		1.7
PromoterAI		0.028	Neutral
Varity_R		0.073
gMVP		0.18
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

hg19: chrX-118108883;