8-12731758-C-T

Position:

• chr8-12731758-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_152271.5(LONRF1):​c.1666G>A​(p.Glu556Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: LONRF1 NM_152271.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.57

Genes affected

LONRF1 (HGNC:26302): (LON peptidase N-terminal domain and ring finger 1) Predicted to enable metal ion binding activity. Predicted to be located in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LONRF1	NM_152271.5	c.1666G>A	p.Glu556Lys	missense_variant	8/12	ENST00000398246.8	NP_689484.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LONRF1	ENST00000398246.8	c.1666G>A	p.Glu556Lys	missense_variant	8/12	5	NM_152271.5	ENSP00000381298.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 06, 2022

The c.1666G>A (p.E556K) alteration is located in exon 8 (coding exon 8) of the LONRF1 gene. This alteration results from a G to A substitution at nucleotide position 1666, causing the glutamic acid (E) at amino acid position 556 to be replaced by a lysine (K). 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	0.28
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.093	T;T;T
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.98	D;D;D
M_CAP	Uncertain	0.10	D
MetaRNN	Uncertain	0.59	D;D;D
MetaSVM	Uncertain	0.48	D
MutationAssessor	Uncertain	2.7	M;.;.
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-3.1	D;D;D
REVEL	Uncertain	0.59
Sift	Uncertain	0.0030	D;T;T
Sift4G	Uncertain	0.013	D;T;T
Polyphen		0.61	P;.;.
Vest4		0.29
MutPred		0.38		Gain of ubiquitination at E556 (P = 0.0138);.;.;
MVP		0.69
MPC		1.7
ClinPred		0.98	D
GERP RS		5.0
Varity_R		0.62
gMVP		0.77

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr8-12589267;